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  • IL-36α contributes to enhanced T helper 17 type responses in allergic rhinitis
    Cytokine (IF 3.078) Pub Date : 2020-01-23
    Xiaowei Qin; Tianhong Zhang; Chunrui Wang; Huijun Li; Ming Liu; Yanan Sun

    Background T helper 17 (Th17) cell subsets, belongs to CD4+ T cell lineage, are proved to be closely related to pathophysiology of AR recently. The interleukin-36 (IL-36) had been reported to promote the up-regulation of Th17 cytokines in psoriasis. We investigated the regulation of Th17 inflammation by IL-36 family cytokines in allergic rhinitis (AR). Methods Twenty-one patients with AR and 20 healthy controls were enrolled. The expression of serum protein and mRNA of IL-36 family cytokines between AR and control group were detected and compared. Human peripheral blood mononuclear cells were purified and stimulated by IL-36 cytokines. The transcription factor and production of Th17 cytokines by Th17 cells were evaluated. Mouse model with AR was established to confirm the in vitro results. Results The serum expression of IL-36 cytokines and Th17 cytokines (IL-17 and IL-23) of AR patients were up-regulated significantly compared with controls. The IL-36α promoted the differentiation and function of Th17 cells. The anti-IL-36α treatment could alleviate the Th17 response in AR mice, presented with alleviated symptoms, decreased infiltration of Th17 cells and down-regulated Th17 cytokines expression. Conclusions IL-36α was involved in the regulation of Th17 responses in allergic rhinitis.

  • Progranulin as a novel biomarker in diagnosis of early-onset neonatal sepsis
    Cytokine (IF 3.078) Pub Date : 2020-01-23
    Lubei Rao; Zhixin Song; Xiaoyan Yu; Qianqian Tu; Yu He; Yetao Luo; Yibing Yin; Dapeng Chen

    Background Infections are leading causes of morbidity and mortality in neonates and may also have severe long-term consequences. As early diagnosis of neonatal sepsis improves prognosis, identification of new or complementary biomarkers is of great importance. In this study, we have evaluated the diagnostic value of progranulin (PGRN) in early-onset neonatal sepsis (EOS) and compare its effectiveness with other commonly used biomarkers, such as procalcitonin (PCT) and C-reactive protein (CRP). Methods A total of 121 infants with gestational age of >34 weeks admitted with suspected EOS were included in this study. Before initiating therapy, blood samples for whole blood count, CRP, PCT and PGRN were obtained from all neonates. Receiver-operating characteristic (ROC) curve and multivariate logistic regression analyses were performed. Results Serum PGRN level of infected group was significantly higher than uninfected group (median 47.72 vs. 37.86 ng/ml, respectively; Mann-Whitney p < 0.0001). The ROC area under the curve (AUC) was 0.786 [95% confidence interval (CI) 0.706–0.867; p < 0.0001] for PGRN, 0.699 (95% CI 0.601–0.797; p = 0.0001) for age adjusted PCT, and 0.673 (95% CI 0.573–0.773; p = 0.0007) for CRP. With a cut-off value of 37.89 ng/ml, the diagnostic sensitivity and negative predictive value of PGRN were 94.34% and 91.7%, respectively. PGRN could significantly predict EOS independently of PCT (p < 0.0001), and the combined use of PGRN and PCT could significantly improve diagnostic performance for EOS (0.806; 95% CI 0.73–0.88; p < 0.0001), with a specificity of 89.06% and a positive predictive value of 81.10%. Conclusions PGRN may be used as a promising biomarker for the diagnosis of EOS, and the combined use of PGRN and PCT could improve the diagnosis of sepsis.

  • Activation of adenosine A2A receptor induced interleukin-23 mRNA expression in macrophages of ankylosing spondylitis patients
    Cytokine (IF 3.078) Pub Date : 2020-01-21
    Maryam Akhtari; Mahdi Vojdanian; Ali Javinani; Amir Ashraf-Ganjouei; Ahmadreza Jamshidi; Mahdi Mahmoudi

    Background Ankylosing spondylitis (AS) is an auto-inflammatory debilitating disorder with a complex pathogenesis. The adenosinergic pathway is an immunologic regulating pathway with a potential role in AS pathophysiology. In the present study, we have aimed to investigate the influence of A2A adenosine receptor (A2AAR) activation on tumor necrosis factor-α (TNF-α) and interleukin-23 (IL-23) expression and secretion by monocyte-generated macrophages of AS patients. Methods Whole-blood separated monocytes were extracted from 14 AS patients and 14 healthy controls. Macrophages were differentiated by macrophage colony-stimulating factor (M-CSF), and surface markers were confirmed by flow cytometer. Cells were treated with CGS-21680 as a known agonist of A2AAR. Analysis of ADORA2A, TNFA, and IL23A gene expression was performed by SYBR green real-time PCR. The concentration of secreted cytokines was also measured by ELISA kits. Results Based on our analysis, CGS-21680 significantly decreased TNF-α secretion by monocyte-derived macrophages of AS patients. Moreover, A2AAR agonist increased the IL23A mRNA expression level in monocyte-derived macrophages of AS patients considerably. Whereas, CGS-21680 did not have any influence on macrophages of healthy individuals. Conclusion According to our results, it appears that A2AAR activation can increase IL-23 secretion by monocyte-derived macrophages of AS patients. Although the TNF-α reducing effect of A2AAR agonists can be a potential target in AS treatment, robust increasing of IL-23 should be considered as the undesirable effect of these agents.

  • Interleukin-2 chronotherapy for metastatic renal cell carcinoma: Results of a phase I-II study
    Cytokine (IF 3.078) Pub Date : 2020-01-20
    Giovanni Lo Re; Davide A. Santeufemia; Francesco Lo Re; Roberto Bortolus; Paolo Doretto; Wally Marus; Lorenzo Buttazzi; Oliviero Lenardon; Alessandra Falda; Rita Piazza; Sandro Sulfaro

    Background Interleukin-2 (IL-2) was the cornerstone treatment for metastatic renal cell carcinoma (RCC) until the advent of tyrosine kinase inhibitors, but it still has therapeutic value. As a single bolus of IL-2 causes toxicity, there is interest in administration regimens with better tolerability and efficacy. Chronotherapy is the administration of therapy according to the circadian rhythm’s influence on the immune and hormonal systems. This phase I-II trial evaluated the safety of IL-2 chronotherapy in metastatic RCC patients and determined the maximum tolerated dose. The secondary objective was to identify prognostic factors for survival. Methods Three chronomodulation schedules (5:00–13:00, 13:00–21:00, and 21:00–5:00) were tested. Each schedule was an 8-h IL-2 infusion, with a Gaussian distribution of drug concentration peaking at 4 h. To identify the maximum tolerated dose, the dose for different patients was escalated from 2 MIU/m2 (level I) to 18.6 MIU/m2 (level VI). Results Thirty patients were enrolled and completed treatment. Two patients were treated at 5:00–13:00, 15 at 13:00–21:00, and 13 at 21:00–5:00. Nine cases of grade 3 toxicity occurred in 7 patients at the highest dose (18.6 MIU/m2); no grade 4 toxicity occurred. The maximum tolerated dose was 14.0 MUI/m2. Patients were followed for a median of 16 months (range, 2–107). One patient was lost to follow-up, 3 patients were alive at last contact, and 26 patients died. Six patients achieved long-term survival (≥48 months). There was one complete response, four partial responses, 11 cases of stable disease and 14 of progressive disease. The response rate was 16% (5/30) and disease-control rate was 53% (16/30). Median progression-free survival was 4.5 months, and median overall survival was 14.5 months. Kaplan-Meier analyses revealed significant associations between overall survival and ECOG performance score (0 vs. 1–2), MSKCC score (0–2 vs. ≥ 3), IMDC risk score (0–2 vs. ≥ 3), IL-2 dose level (IV-VI vs. I-III), and prolactin (increase vs. no increase), and but not for chronotherapy schedule. Conclusion IL-2 chronotherapy appears to be safe, moderately toxic and active in metastatic RCC. It may represent a new modality of IL-2 administration for these patients.

  • Secreted protein acidic and rich in cysteine and cancer: A homeostatic hormone?
    Cytokine (IF 3.078) Pub Date : 2020-01-16
    Abdelaziz Ghanemi; Mayumi Yoshioka; Jonny St-Amand
  • Promoter polymorphisms in IL-6 gene influence pro-inflammatory cytokines for the risk of osteoarthritis
    Cytokine (IF 3.078) Pub Date : 2020-01-14
    Monica Singh; Sarabjit Mastana; Surinderpal Singh; Pawan Kumar Juneja; Taranpal Kaur; Puneetpal Singh

    Background Interleukin-6 (IL-6) gene regulates IL-6 levels, interplay of which has been found to influence pathophysiology of osteoarthritis (OA). Polymorphism within promoter region of IL-6 gene and its association with plasma levels of pro-inflammatory cytokines; IL-6, interleukin 1-beta (IL-1β) and tumor necrosis factor–alpha (TNF-α) remained to be investigated in Punjab region of India, where OA is highly prevalent. Methods Six single nucleotide polymorphisms (SNPs) in the promoter region of IL-6 gene; rs1800795 (−174G/C), rs1800796 (−572G/C), rs1800797 (−597G/A), rs2069827 (−1363G/T), rs12700386 (−2954G/C) and rs10499563 (−6331G/T) were investigated by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 279 confirmed osteoarthritis patients and 287 controls. Plasma levels of pro-inflammatory cytokines; IL-6, IL-1β and TNF-α were measured by sandwich Enzyme Linked Immunosorbent Assay (ELISA). Results Allele frequency spectrum after adjusting the effect of systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein (LDL), triglycerides (TG) and body mass index (BMI) revealed that major allele G of rs1800795 and T of rs10499563 were significantly associated with increased risk of OA (P < 0.01) in all the three genetic models; co-dominant (OR 4.08 & 4.12, P < 0.001), recessive (OR 3.00 & 2.51, P < 0.001) and dominant (OR 2.56 & 3.09, P < 0.05). Major allele G of rs1800796 and rs1800797 was observed to enhance OA risk in recessive mode (OR 1.75, P < 0.001 & 1.62, P = 0.01 respectively). Disease risk analysis after adjusting the effect of confounders exposed a susceptibility haplotype GGGGCT, which increased the OA risk by 2.27 times (OR 2.27, 95%CI: 1.26–4.10, P = 0.009) and a protective haplotype CGAGGC which significantly reduced the OA risk (OR 0.47, 95%CI 0.27–0.92, P = 0.031). Both of these haplotypes manifested in the recessive mode of inheritance. Subjects who had one copy of the susceptibility haplotype had lower values of IL-6 (3.6 pg/ml) and IL-1β levels (3.2 pg/ml) than those who had 2 copies of it (4.4 pg/ml & 4.2 pg/ml respectively). IL-6 and IL-1β levels were observed to be negatively associated with protective haplotype CGAGGC (P < 0.05). Carriers of 1 copy of this haplotype showed decreased IL-1β levels than those who had none (1.00 pg/ml vs. 1.3 pg/ml respectively) which further decreased to 0.9 pg/ml in those subjects who carried two copies of protective haplotype. Conclusion The present study discovered susceptibility (GGGGCT) and protective (CGAGGC) haplotypes within promoter region of IL-6 gene which influenced the plasma levels of IL-6 and IL-1β for the risk of osteoarthritis in the population of Punjab, India.

  • 更新日期:2020-01-14
  • Interleukin-17 mRNA expression and serum levels in Behçet’s disease
    Cytokine (IF 3.078) Pub Date : 2020-01-14
    Golamreza Jadideslam; Houman Kahroba; Khalil Ansarin; Ebrahim Sakhinia; Alireza Abhar; Shahriar Alipour; Jafar Farhadi; Sam Seydi Shirvani; Masoud Nouri-Vaskeh; Saeed Mousavi; Alireza khabbazi

    Behçet’s disease (BD) was considered a T-helper 1 (Th1)-mediated autoimmune disease, but with the introduction of Th17 cells, their role in the pathogenesis of BD was also addressed. Despite studies on IL-17 in BD, the prognostic value of this cytokine in BD is unclear. The aim of this study is to determine the IL-17 mRNA expression rate and serum levels in patients with BD and its correlation with clinical manifestations and activity of BD. Forty-six BD patients in the active phase of the disease and 70 healthy controls were recruited in this study. BD activity was measured by Behçet’s disease current activity form (BDCAF), Iranian Behçet’s disease dynamic activity measure (IBDDAM) and total inflammatory activity index (TIAI). The IL-17 mRNA expression and serum levels were significantly higher in the BD patients compared with the healthy controls. These parameters in the BD patients aged <25 at disease onset, positive pathergy test, and positive HLA-B5 and HA-B51 were significantly higher than the healthy controls (P < 0.05). The IL-17 serum level in the patients with active uveitis was lower than the patients with in-active uveitis. There was no association between other clinical manifestations of BD and these parameters. No significant correlation was found between BDCAF and IBDDAM with IL-17 mRNA expression and serum levels. However, TIAI had a significant and negative correlation with the serum levels of IL-17.

  • Effects of maternal and fetal vascular endothelial growth factor a single nucleotide polymorphisms on pre-eclampsia: A hybrid design study
    Cytokine (IF 3.078) Pub Date : 2020-01-14
    Xian Zhen Chen; Shao Jing Yu; Mu Hong Wei; Chen Yang Li; Wei Rong Yan

    Maternal and fetal gene variants play important roles in the pathology of pre-eclampsia (PE), but most studies investigating the associations between vascular endothelial growth factor A (VEGF-A) gene variates and PE focusing on maternal genetic effects. The present study firstly used a hybrid case-parent and control-mother study design investigating the both maternal and fetal effects of VEGF-A gene polymorphisms on PE among Han Chinese pregnant women. This study recruited 221 PE patients with their partners and infants and 345 normotensive women with their infants. The current study found that, in both maternal and fetal dominant model (GC + CC/GG), VEGF-A rs2010963 polymorphism was associated with an increased risk of PE (OR = 1.85, 95% CI: 1.25–2.75; OR = 1.90, 95% CI: 1.28–2.83, respectively). In the log-liner model analyses, offspring carrying the genotype of GC or CC in the rs2010963 polymorphism could increase the risk of maternal PE (OR = 1.84, 95%CI: 1.18–2.86; OR = 1.89, 95%CI: 1.02–3.49, respectively) compared to the offspring with GG. Meanwhile, the present study also found that passive smoking had a significant interaction with maternal rs2010963 polymorphism (PLRT = 0.022) on the risk of PE.

  • Ocular toxoplasmosis associated with up-regulation of miR-155-5p/miR-29c-3p and down-regulation of miR-21-5p/miR-125b-5p
    Cytokine (IF 3.078) Pub Date : 2020-01-13
    Cristina Silva Meira-Strejevitch; Ingrid de Siqueira Pereira; Daise Damaris Carnietto Hippólito; Marta Marques Maia; Allecineia Bispo Cruz; Ricardo Gava; Cinara Cássia Brandão de Mattos; Fábio Batista Frederico; Rubens Camargo Siqueira; Luiz Carlos Mattos; Vera Lucia Pereira-Chioccola
  • Levels of pro- and anti-inflammatory cytokines in cystic fibrosis patients with or without gingivitis
    Cytokine (IF 3.078) Pub Date : 2020-01-09
    Onurcem Duruel; Ezel Berker; Cansu Özşin-Özler; Mina Gharibzadeh-Hızal; Öznur Gürpınar; Sanem Eryılmaz-Polat; Emel Tuğba Ataman-Duruel; Çağman Tan; Erdem Karabulut; Meryem Tekçiçek; Özgen Köseoğlu-Eser; Nural Kiper; İlhan Tezcan

    Background Inflammatory periodontal diseases are caused by interaction between gram negative, anaerobic bacteria and host response. Persistent infection of Pseudomonas aeruginosa in cystic fibrosis (CF) patients also cause increased pro-inflammatory response and the imbalance of pro- and anti-inflammatory response in brochoalveolar lavage fluid which leads to destruction of lungs. The aim of this study is to evaluate periodontal status of CF patients, to measure level of cytokines and biochemical molecules in gingival crevicular fluid (GCF), and to detect presence of P. aeruginosa in dental plaque samples. Materials and methods GCF samples were collected from 41 CF patients and 39 healthy (non-CF) subjects. Interleukin (IL)-1ß, IL-17, IL-10, human neutrophil elastase (HNE), cystic fibrosis transmembrane regulator (CFTR) protein, and human β-defensin-1 (HBD1) in GCF were evaluated by ELISA method. Dental plaque samples were collected from 18 CF patients with history of P. aeruginosa colonization and 15 non-CF subjects. Presence of P. aeruginosa was evaluated by using conventional culture methods and molecular methods. Results Levels of IL-1ß, HNE, and HBD1 in CF patients were significantly higher than non-CF subjects. However, IL-10 level was significantly lower in CF patients. Increased pro-inflammatory (IL-1ß) and decreased anti-inflammatory (IL-10) cytokine levels were observed in GCF samples from CF patients, irrespective of their periodontal status. P. aeruginosa were detected in four samples of 18 CF patients, and all were negative in non-CF group. Conclusions As a result of this study, CF coexists increasing pro-inflammatory and decreasing anti-inflammatory response locally. Due to increasing pro-inflammation, CF patients should be followed-up more often than non-CF children.

  • Interleukin-38 is elevated in inflammatory bowel diseases and suppresses intestinal inflammation
    Cytokine (IF 3.078) Pub Date : 2020-01-09
    Cheng Xie; Wei Yan; Runze Quan; Chaoyue Chen; Lei Tu; Xiaohua Hou; Yu Fu

    There has been no report investigating the role of IL-38 in inflammatory bowel diseases (IBD). Therefore, we investigated the expression of IL-38 in IBD patients and its role in regulating intestinal inflammation. The levels of IL-38 were significantly elevated in the intestine of IBD patients and DSS-induced colitis mice. Immunofluorescence analysis revealed that B cell, not macrophage or T cell, was the source of IL-38 in the intestine. We found that rIL-38 treatment significantly attenuated DSS-induced colitis, including alleviation of weight loss, disease activity index, macroscopic changes and histological damage of colon, along with lower levels of IL-1β and TNF-α. In vitro, rIL-38 significantly decreased the expression of proinflammatory cytokines in LPS-stimulated RAW 264.7 cells and BMDM. This is the first study suggesting that IL-38 may have a protective effect in IBD, which inhibits the production of proinflammatory cytokines from macrophages. IL-38 may represent a promising therapeutic strategy in IBD.

  • Macrophage activity is associated with gingival inflammation: Soluble CD163 in an experimental gingivitis study
    Cytokine (IF 3.078) Pub Date : 2020-01-06
    Gustavo G. Nascimento; Holger J. Møller; Rodrigo López

    Aim This study aimed to investigate the association between gingival inflammation and levels of soluble CD163 (sCD163), a macrophage-specific marker associated to inflammation, in young adults participating in an experimental gingivitis study. Methods Forty-two university students volunteered to participate in the study, which comprised three phases: a two-week Hygiene Phase (clinical examination and professional cleaning); a three-week Induction Phase (absence of oral hygiene); and a two-week Resolution Phase (reestablishment of oral hygiene). Clinical recordings of plaque (Modified Quigley and Hein Plaque Index) and gingival inflammation (Modified Gingival Index) were collected weekly during the Induction Phase, and after two weeks during the Resolution Phase. Levels of sCD163 from gingival crevicular fluid (GCF) were collected during Induction and Resolution Phases and measured by ELISA. Group-based-trajectory-modeling (GBTM) was used to model patterns of sCD163 throughout the Induction Phase. Mixed-effects multilevel models were used to estimate the effect of gingival inflammation on sCD163 over time. Results Levels of sCD163 increased steadily over time, however, sCD163 showed a lagged response to gingival inflammation. GBTM analysis identified two groups for sCD163: one with a “linear” trajectory of sCD163 over the Induction Phase (n = 35), and another with a “quadratic” (n = 7) increase of sCD163 at the end of the Induction Phase. Stratified analysis by the sCD163 groups revealed that “linear” sCD163 growth was associated with both GCF volume and gingival inflammation but lagged in time, while a “quadratic” growth was associated with gingival inflammation and time. Conclusions Macrophage activity is associated with gingival inflammation and can be detected at early stages of gingivitis. However, while in most participants a “linear” trajectory of sCD163 over the development of gingival inflammation was observed, among few individuals an exacerbated increase of sCD163 levels in GCF was noticed particularly at the end of the Induction Phase.

  • IκBζ controls NLRP3 inflammasome activation via upregulation of the Nlrp3 gene
    Cytokine (IF 3.078) Pub Date : 2020-01-07
    Jeongeun Kim; Huijeong Ahn; Sangjung Yu; Jae-Hee Ahn; Hyun-Jeong Ko; Mi-Na Kweon; Eui-Ju Hong; Beum-Soo An; Eunsong Lee; Geun-Shik Lee

    Inflammasome activation induces the maturation and secretion of interleukin (IL)-1β and -18, and is dependent on NF-κB signaling to induce the transcription of the inflammasome components, called the priming step. This study elucidated the role of IκBζ, an atypical IκBs (inhibitor of κB) and a coactivator of NF-κB target genes, on the activation of inflammasome. Bone marrow-derived macrophages (BMDMs) that originated from IκBζ-encoding Nfkbiz gene depletion mice presented a defect in NLRP3 inflammasome activation. In addition, the Nfkbiz+/− and Nfkbiz−/− mice significantly attenuated serum IL-1β secretion in response to a monosodium urate injection, a NLRP3 trigger, when compared with Nfkbiz−+/+ mice. The lack of IκBζ in BMDMs produced a disability in the expression of Nlrp3 and pro-Il1β mRNAs during the priming step. In addition, ectopic IκBζ expression enhanced the Nlrp3 promoter activity, and Nlrp3 and pro-Il1β transcription. Overall, IκBζ controlled the activation of NLRP3 inflammasome by upregulating the Nlrp3 gene during the priming step.

  • Immunostimulatory effect of chitosan conjugated green copper oxide nanoparticles in tumor immunotherapy
    Cytokine (IF 3.078) Pub Date : 2020-01-07
    Aditi Dey; Subhankar Manna; Sunil Kumar; Sourav Chattopadhyay; Bhaskar Saha; Somenath Roy

    Current study demonstrates the immunogenic role of biopolymer coated green synthesized copper oxide nanoparticles by the induction of cellular immunity through the activation immune cells. Alongside humoral immunity response was triggered by the surface coated NPs through IgG response which indicate the adjuvanic role of the nano conjugate. Th1 (Type 1 and Type 2 helper T cells) and Th2 cells were activated after the treatment with nano conjugate and act as an immunostimulant which would inhibit the proliferation of breast cancer (MCF-7) and cervical cancer (HeLa) cells in in vitro. Solid tumor induced by 4 T1 cells were also inhibited in in vivo Balb/C mice model. Secretion of pro-inflammatory cytokines and the increase in CD + 4 populations indicate the activation of immune cells in the current study. Immunotherapy by the help of metal nano conjugate can be an effective tool to eradicate the cancer cells from the system.

  • IL-33 and ST2 as predictors of disease severity in children with viral acute lower respiratory infection
    Cytokine (IF 3.078) Pub Date : 2020-01-03
    Carolina Augusta Arantes Portugal; Ítalo de Araújo Castro; Mirela Cristina Moreira Prates; Talita Bianca Gagliardi; Ronaldo Bragança Martins; Bruna Laís Santos de Jesus; Ricardo de Souza Cardoso; Marcus Vinícius Gomes da Silva; Davi Casale Aragon; Eurico Arruda Neto; José Carlos Farias Alves Filho; Fernando de Queiroz Cunha; Ana Paula de Carvalho Panzeri Carlotti

    Background Mechanisms influencing severity of acute lower respiratory infection (ALRI) in children are not established. We aimed to assess the role of inflammatory markers and respiratory viruses in ALRI severity. Methods Concentrations of interleukin(IL)-33, soluble suppression of tumorigenicity (sST)2, IL-1ß, tumor necrosis factor α, IL-4, IL-6 and IL- 8 and types of respiratory viruses were evaluated in children at the first and fifth days after hospital admission. Disease severity was defined as need for mechanical ventilation. Results Seventy-nine children <5 years-old were included; 33(41.8%) received mechanical ventilation. No associations between virus type, viral load or co-detections and severity of disease were observed. Detection of IL-33 and sST2 in nasopharyngeal aspirates (NPA) on admission were associated with higher risk for mechanical ventilation (RR = 2.89 and RR = 4.57, respectively). IL-6 and IL-8 concentrations were higher on Day 5 in mechanically ventilated children. IL-6 NPA concentrations decreased from Day 1 to Day 5 in children who did not receive mechanical ventilation. Increase in sST2 NPA concentrations from Day 1 to Day 5 was associated with longer hospital length of stay (p < 0.01). Conclusions An exacerbated local activation of the IL-33/ST2 axis and persistently high sST2 concentrations over time were associated with severity of viral ALRI in children.

  • Prognostic value of visfatin in various human malignancies: A systematic review and meta-analysis
    Cytokine (IF 3.078) Pub Date : 2020-01-02
    Masoumeh Mohammadi; Ali Moradi; Javad Farhadi; Abolfazl Akbari; Shokoufeh Pourmandi; Hassan Mehrad-Majd

    Although numerous studies have shown that visfatin is linked to several cancers, its prognostic value is still unclear. This first comprehensive meta-analysis was performed to evaluate the prognostic effect of visfatin in cancer patients. A systematic search was conducted for relevant studies in health-related electronic databases up to May 2019. The pooled hazard ratios (HRs) and ORs with 95% confidence intervals (CIs) for total and stratified analyses were calculated to demonstrate the prognostic value of visfatin expression level in cancer patients. Heterogeneity and publication bias were also investigated. A total of 14 eligible studies with 1616 patients were included in the current meta-analysis. Pooling results revealed that, high visfatin expression was significantly associated with poorer overall survival (OS) (HR = 2.43, 95% CI 1.64–3.62, P < 0.001). Elevated visfatin level was also correlated with positive lymph node metastasis (OR = 2.45, 95% CI 1.43–4.17, P ≤ 0.001), positive distance metastasis (OR = 2014, 95% CI 1.25–3.69, P ≤ 0.001), advanced tumor stage (OR = 3.01, 95% CI 1.91–7.72, P ≤ 0.001), and larger tumor size (OR = 1.99, 95% CI 1.49–2.69, P ≤ 0.001). Our meta-results indicates that altered visfatin expression is a potential indicator of poor clinical outcomes in tumor patients, suggesting that high visfatin expression may serve as a potential biomarker of poor prognosis and metastasis in cancers.

  • Association between IL-27 and Tr1 cells in severe form of paracoccidioidomycosis
    Cytokine (IF 3.078) Pub Date : 2020-01-02
    Lívia Moreira Genaro; Lilian de Oliveira Coser; Amauri da Silva Justo Junior; Livia Furquim de Castro; Anne Karine Felício Barreto; Angela Eugênia Rizzato; Plínio Trabasso; Ronei Luciano Mamoni; Ricardo Mendes Pereira; Maria Letícia Cintra; Luana Nunes Santos; Murilo de Carvalho; Luciana Pereira Ruas; Maria Heloisa de Souza Lima Blotta

    Interleukin-27, a cytokine of the IL-12 family, is secreted by antigen-presenting cells such as macrophages and dendritic cells (DCs). Recent studies suggest an anti-inflammatory role for IL-27 by inducing IL-10 producing Tr1 cells capable of inhibiting Th1 and Th17 type responses. Our study aimed to investigate the involvement of IL-27 and Tr1 cells in the immunomodulation of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Brazil. The presence of IL-27 was evaluated in serum and biopsies of patients with PCM by ELISA, immunohistochemistry, and immunofluorescence. The presence of Tr1 in peripheral blood was analyzed by flow cytometry. In vitro assays were performed to verify the ability of P. brasiliensis yeast to induce IL-27 production by DCs and macrophages, as well as the polarization of lymphocytes to the Tr1 phenotype. Patients with the acute form and severe chronic form, the most severe and disseminated forms of PCM, presented higher serum concentrations of IL-27 and higher percentage of Tr1 cells compared to patients with mild chronic form. IL-27 was also detected in lesions of patients with PCM and associated with DCs and macrophages. P. brasiliensis Pb18 yeasts were able to induce IL-27 production by both DCs and macrophages. We found that DCs pulsed with Pb18 were able to induce Tr1 lymphocytes in vitro. Our data suggest that IL-27 and Tr1 cells could contribute to the deficient immune response to P. brasiliensis that leads to severe and disseminated forms of the disease.

  • 更新日期:2020-01-02
  • Antiviral responses against chicken respiratory infections: Focus on avian influenza virus and infectious bronchitis virus
    Cytokine (IF 3.078) Pub Date : 2019-12-31
    Neda Barjesteh; Kelsey O'Dowd; Seyed Milad Vahedi

    Some of the respiratory viral infections in chickens pose a significant threat to the poultry industry and public health. In response to viral infections, host innate responses provide the first line of defense against viruses, which often act even before the establishment of the infection. Host cells sense the presence of viral components through germinal encoded pattern recognition receptors (PRRs). The engagement of PRRs with pathogen-associated molecular patterns leads to the induction of pro-inflammatory and interferon productions. Induced antiviral responses play a critical role in the outcome of the infections. In order to improve current strategies for control of viral infections or to advance new strategies aimed against viral infections, a deep understanding of host-virus interaction and induction of antiviral responses is required. In this review, we summarized recent progress in understanding innate antiviral responses in chickens with a focus on the avian influenza virus and infectious bronchitis virus.

  • Interactions among thyroid hormone (FT4), chemokine (MCP-1) and neurotrophin (NGF-β) levels studied in Hungarian postmenopausal and obese women
    Cytokine (IF 3.078) Pub Date : 2019-12-31
    Ildikó Molnár

    Thyroid dysfunction is more frequent in postmenopause and metabolic syndrome characterized by increased proinflammatory cytokines (IL-1, IL-6, TNFα), insulin resistance and overweight. Serum levels of monocyte chemoattractant protein-1 (MCP-1) chemokine and nerve growth factor-β (NGF-β) and their effects were studied on thyroid hormone levels in 133 Hungarian women (postmenopausal 66, obese 32, control 35). MCP-1 and NGF-β levels were measured with enzyme-linked, and thyroid hormones with chemiluminescence immunoassays. Subclinical hypothyroidism in postmenopause (7/66 vs 1/32 cases) and the presence of low FT4 levels in obese women were more frequent (6/32 vs 2/66 cases, p < 0.0447). Obese women showed reduced serum FT4 and higher MCP-1 or NGF-β levels compared to those in postmenopausal women [geometric mean (95%CI): 13.6 (10.9–21.69) vs 15.37 (9.06–20.42) pmol/l, p < 0.003 for FT4, and 19.36 (14.27–26.26) vs 17.29 (12.65–23.63) ng/ml, p < 0.0013 for MCP-1 or 18.64 (6.8–51.11) vs 14.01 (8.59–22.83) ng/ml, p < 0.0003 for NGF-β]. Serum FT4 levels inversely associated with MCP-1 (p < 0.0023, r = −0.1971) or estradiol levels (p < 0.0286, r = −0.1913), and positively associated with age (p < 0.0175, r = 0.2058). As opposed to estradiol and NGF-β levels, BMI had no effects on serum FT4 levels in postmenopausal and obese women forming 3 subgroups displaying only MCP-1, both MCP-1 and NGF-β positivities or no positivities at all. In summary, not only proinflammatory cytokines, but also MCP-1 chemokine and NGF-β levels can play a role in reduced serum FT4 levels in postmenopausal and obese women. Particularly, the decreased FT4 levels were connected to both increased MCP-1 and NGF-β levels in obese women.

  • Extremely high levels of multiple cytokines in the cord blood of neonates born to mothers with systemic autoimmune diseases
    Cytokine (IF 3.078) Pub Date : 2019-12-19
    Naoto Takahashi; Takeshi Nagamatsu; Tatsuya Fujii; Kayo Takahashi; Yumi Tsuchida; Keishi Fujio; Tomoyuki Fujii

    Most infants born to mothers with autoimmune diseases are thought to be entirely healthy. However, the immunological conditions have not been examined thoroughly. Fourteen neonates born to mothers with systemic autoimmune diseases, namely systemic lupus erythematosus, mixed connective tissue disease, Sjögren’s syndrome, rheumatoid arthritis, and systemic sclerosis, were included. Serum concentrations of 17 cytokines from the infants’ umbilical artery (UA) and vein (UV) and from the mothers’ peripheral blood were investigated by a bead array system. Cytokine expression in the placenta was investigated by immunohistochemical staining. The disease was controlled in all mothers, and none had chorioamnionitis. Hypercytokinemia was found in 11 neonates irrespective of their mothers’ autoimmune diseases. In six neonates, serum cytokines were at extremely high levels. Four neonates were born by cesarean section because of a non-reassuring fetal status (NRFS) of unknown cause were all included in the hypercytokinemia group. However, all the subjects were discharged without any complications. The cytokine levels were almost the same between UA and UV, but the mothers’ blood samples did not show elevation of serum cytokines. There were no differences in the expression of cytokines in the placenta among three patients with different serum cytokines levels. Hypercytokinemia frequently occurred and a cytokine storm state sometimes developed in neonates born to mothers with systemic autoimmune diseases. Growth restriction and NRFS may be related to hypercytokinemia in utero. It is plausible that the high level of cytokines in cord blood originate in neither the mother nor the placenta but in fetal immune tissues. It is important to investigate the immunological mechanisms, prevalence, and long-term influence of hypercytokinemia in a large sample size of neonates and mothers with systemic autoimmune diseases.

  • Locally-secreted interleukin-6 is related with radiological severity in smear-negative pulmonary tuberculosis
    Cytokine (IF 3.078) Pub Date : 2019-12-25
    Paula Ximena Losada; Federico Perdomo-Celis; Marcela Castro; Carol Salcedo; Arnold Salcedo; Isabel DeLaura; Giovani Lastra; Carlos F. Narváez

    Pulmonary tuberculosis (PTB) has been identified as a substantial public health threat and diagnostic challenge. A large proportion of patients exhibit negative smear tests despite active infection. The role of cytokines in the pathophysiology and clinical severity of PTB remains a controversial question. We evaluated the pattern of cytokines presents locally in patients with smear-negative PTB. Levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-6, IL-10, and IL-17 in bronchoalveolar lavage fluid (BALf) from patients with smear-negative PTB, as well as in those with other pulmonary diseases and controls, were performed by flow cytometry. ROC curve and a radiological severity scale were used to establish the potential diagnosis use and the relationship of the cytokine levels with disease severity, respectively. The levels of IL-6 were higher in the PTB (P = 0.0249) and pneumonia (P = 0.0047) groups compared to controls. Low to undetectable levels of TNF-α, IFN-γ, IL-2, IL-4, IL-10, and IL-17 were found in BALf, even after sample concentration using filtration columns and centrifugation. IL-6 levels measured in BALf could distinguish PTB patients or pneumonia patients from controls (AUC: 0.91, P = 0.002 and AUC: 0.86, P = 0.001, respectively), but not patients with PTB from those with pneumonia (AUC: 0.51, P = 0.86). IL-6 levels were related with the severity of PTB, as levels were higher in patients with higher radiological severity. These results confirm the importance of IL-6 in the immunopathology of smear-negative PTB.

  • Chemokines in human obesity
    Cytokine (IF 3.078) Pub Date : 2019-12-19
    Volatiana Rakotoarivelo; Bhavesh Variya; Marie-France Langlois; Sheela Ramanathan

    Obesity and type 2 diabetes have been shown to be associated with chronic inflammation. Despite extensive evidence for inflammatory mediators in the obese patients and multiple clinical trials, the outcome has been disappointing. In murine models recruitment of immune cells during inflammation has been shown to contribute to the chronic inflammation. Clearcut evidence for the differential expression of chemokines that mediate this recruitment is not available. In this short review we discuss the observations on CCL2 and CCL5 in human obesity.

  • 更新日期:2019-12-26
  • Agomelatine could prevent brain and cerebellum injury against LPS-induced neuroinflammation in rats
    Cytokine (IF 3.078) Pub Date : 2019-12-20
    M. Savran; R. Aslankoc; O. Ozmen; Y. Erzurumlu; H.B. Savas; E.N. Temel; P.A. Kosar; S. Boztepe

    Sepsis, systemic hyper-inflammatory immune response, causes the increase of morbidity and mortality rates due to multi-organ diseases such as neurotoxicity. Lipopolysaccharide (LPS) induces inflammation, oxidative stress and apoptosis to cause brain damage. We aimed to evaluate the antioxidant, anti-inflammatory and antiapoptotic effects of Agomelatine (AGM) on LPS induced brain damage via NF-kB signaling. Twenty-four animals were divided into three groups as control, LPS (5 mg/kg) and LPS + AGM (20 mg/kg). Six hours after the all administrations, rats were sacrificed, brain tissues were collected for biochemical, histopathological and immunohistochemical analysis. In LPS group; total oxidant status (TOS), OSI index, Caspase-8 (Cas-8), NF-kß levels increased and Total antioxidant status (TAS) levels decreased biochemically and Cas-8, haptoglobin and IL-10 expressions increased and sirtuin-1 (SIRT-1) levels decreased immunohistochemically. AGM treatment reversed these parameters except haptoglobin levels in hippocampus and SIRT-1 levels in cerebellum. Besides, AGM treatment blocked the phosphorylation of NF-kB biochemically and ameliorated increased the levels of hyperemia, edema and degenerative changes histopathologically. In conclusion, AGM enhanced SIRT-1 levels to negatively regulate the transcription and activation of p-NF-kB/p65 which caused to ameliorate inflammation, oxidative stress and apoptosis.

  • Effects of daphnetin on the autophagy signaling pathway of fibroblast-like synoviocytes in rats with collagen-induced arthritis (CIA) induced by TNF-α
    Cytokine (IF 3.078) Pub Date : 2019-12-19
    Huimin Deng; Mao Zheng; Ziling Hu; Xiaoping Zeng; Nanzhen Kuang; Yingyuan Fu

    Daphnetin (DAP), an active ingredient extracted from Daphne odora, has pharmacological effects such as anti-inflammatory, antioxidation and anti-tumor properties. The current study aims to investigate the relationship between the anti-rheumatoid effect of DAP and the inhibition of both the PI3K/AKT/mTOR and autophagy signaling pathways. DAP inhibited the proliferation of CIA-FLS in a dose-dependent manner and induce apoptosis, accelerated the G1/G0 phase and inhibited the S phase. DAP reduced the phosphorylation of AKT and mTOR and the expression of Atg5, Beclin-1 and LC3-II/LC3-I in CIA-FLS induced by TNF-α. DAP also reduced the inflammatory response in CIA-FLS induced by TNF-α by inhibiting the cytokine expression of TNF-α, IL-6, TGF-β, IL-17, and INF-γ and promoting IL-10 expression. Overall, DAP inhibited the proliferation of CIA-FLS by down-regulating the PI3K/AKT/mTOR signaling pathway and inhibited autophagy in order to induces apoptosis, which may be potential therapeutic approach in treatment of RA.

  • ER stress contributes to autophagy induction by adiponectin in macrophages: Implication in cell survival and suppression of inflammatory response
    Cytokine (IF 3.078) Pub Date : 2019-12-23
    Hye Jin Oh; Sumin Lee; Pil-Hoon Park

    Adiponectin, the most abundant adipokine, exhibits various physiological functions. In addition to its critical role in lipid metabolism, recent studies have demonstrated its potent anti-inflammatory and cytoprotective properties. Accumulating evidence suggests that autophagy plays a critical role in various biological responses by adiponectin. However, the underlying mechanisms remain elusive. Herein, we investigated the role of ER stress in adiponectin-induced autophagy and its functional roles in biological responses by adiponectin in macrophages. In this study, globular adiponectin (gAcrp) significantly increased the expression of various ER stress markers in both RAW 264.7 and primary peritoneal macrophages. In addition, inhibition of ER stress by treatment with tauroursodeoxycholic acid (TUDCA) or gene silencing of CHOP prominently suppressed gAcrp-induced autophagy. Treatment with gAcrp also induced significant increase in sestrin2 expression. Interestingly, knockdown of sestrin2 prevented autophagy induction and inhibition of ER stress abrogated sestrin2 induction by gAcrp, collectively implying that ER stress critically contributes to gAcrp-induced autophagy activation via sestrin2 induction. Moreover, pretreatment with TUDCA restored suppression of TNF-α and IL-1β expression and attenuated the enhanced viability of macrophages induced by gAcrp. Taken together, these findings indicate the potential role of ER stress in autophagy activation, modulation of inflammatory responses, and cell survival by gAcrp in macrophages.

  • Bulk and single cell transcriptomic data indicate that a dichotomy between inflammatory pathways in peripheral blood and arthritic joints complicates biomarker discovery
    Cytokine (IF 3.078) Pub Date : 2019-12-24
    Eun Jung Lee; Sandra Lilja; Xinxiu Li; Samuel Schäfer; Huan Zhang; Mikael Benson

    Background Unbiased studies using different genome-wide methods have identified several novel biomarkers for diagnosis and treatment response in Rheumatoid Arthritis (RA). However, clinical translation has proven difficult. Here, we hypothesized that one reason could be that inflammatory responses in peripheral blood are different from those in the arthritic joint. Methods We performed meta-analysis of gene expression microarray data from synovium, whole blood cells (WBC), peripheral blood mononuclear cells (PBMC), and CD4+ T cells from patients with RA and healthy controls in order to identify overlapping pathways, upstream regulators and potential biomarkers. We also analyzed single cell RNA-sequencing (scRNA-seq) data from peripheral blood and whole joints from a mouse model of antigen-induced arthritis. Results Analyses of two profiling data sets from synovium from RA patients and healthy controls all showed significant activation of pathways with known pathogenic relevance, such as the Th1 pathway, the role of NFAT in regulation of the immune response, dendritic cell maturation, iCOS-iCOSL signaling in T helper cells, Fcγ receptor-mediated phagocytosis, interferon signaling, Cdc42 signaling, and cytotoxic T lymphocyte-mediated apoptosis. The most activated upstream regulators included TNF, an important drug target, as well as IFN-gamma and CD40LG, all of which are known to play important pathogenic roles in RA. The differentially expressed genes from synovium included several potential biomarkers, such as CCL5, CCL13, CCL18, CX3CL1, CXCL6, CXCL9, CXCL10, CXCL13, IL15, IL32, IL1RN, SPP1, and TNFSF11. By contrast, microarray studies of WBC, PBMC and CD4+ T cells showed variable pathways and limited pathway overlap with synovium. Similarly, scRNA-seq data from a mouse model of arthritis did not support that inflammatory responses in peripheral blood reflect those in the arthritic joints. These data showed pathway overlap between mouse joint cells and synovium from patients with RA, but not with cells in peripheral blood. Conclusions Our findings indicate a dichotomy between gene expression changes, pathways, upstream regulators and biomarkers in synovium and cell types in peripheral blood, which complicates identification of biomarkers in blood.

  • Genetic polymorphism rs8193036 of IL17A is associated with increased susceptibility to pulmonary tuberculosis in Chinese Han population
    Cytokine (IF 3.078) Pub Date : 2019-12-18
    Wenfei Wang; Guofang Deng; Guoliang Zhang; Ziqi Yu; Fan Yang; Jianyong Chen; Yi Cai; Oliver Werz; Xinchun Chen

    Th17 cells play a key role in immunity against Mycobacterium tuberculosis, our previous research showed that reduced Th17 responses were associated with the severe outcome of Mtb infection. The associations between IL17A polymorphisms and susceptibility of TB has been reported, but the results are inconsistent and the underlying mechanisms is unknown. In this study, we identified a genetic variation (rs8193036) in the promoter region of IL17A is associated with susceptibility to TB. The minor allele T frequency of rs8193036 was significantly different between patients with active TB (29.7%) and healthy controls (32.3%) (OR = 0.81; 95%CI, 0.71–0.93; P = 0.0026). Peripheral blood mononuclear cells from individuals carrying rs8193036CC genotypes produced significantly lower amount of IL17A upon CD3/28 stimulation compared to the individuals carrying rs8193036TT genotypes. Functional assay by reporter luciferase activity and EMSA demonstrated that rs8193036C exhibited significantly lower promotor transcription activities. In conclusion, our study confirmed that IL17A (rs8193036) is a functional SNP that could regulate gene expression though influencing transcription factor binding activity.

  • EFLA 945 restricts AIM2 inflammasome activation by preventing DNA entry for psoriasis treatment
    Cytokine (IF 3.078) Pub Date : 2019-12-11
    I-Che Chung, Sheng-Ning Yuan, Chun-Nan OuYang, Sheng-I Hu, Hsin-Chung Lin, Kuo-Yang Huang, Wei-Ning Lin, Yu-Ting Chuang, Yu-Jen Chen, David M. Ojcius, Yu-Sun Chang, Lih-Chyang Chen

    Psoriasis is a chronic inflammatory skin disease that affects about 2% of the general population. Activation of the Absent in Melanoma 2 (AIM2) inflammasome is crucial for immune defense, but it can also cause inflammatory and autoimmune diseases, including psoriasis. We currently lack an AIM2 inflammasome inhibitor that could be used therapeutically. Here, we show that EFLA 945, a safe product of red grape vine leaf extracts, can restrict AIM2 inflammasome activation. Mechanistically, EFLA945 prevents DNA entry into THP-1-derived macrophages, and thereby inhibits cytoplasmic DNA-dependent apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization, caspase-1 activation, and the secretion of interleukin (IL)-1β and IL-18. The major phytochemicals of EFLA 945, resveratrol and peonidin 3-O-glucoside (P3G), appear to be the potential bioactive compounds responsible for its ability to restrict AIM2-dependent IL-1β secretion. Importantly, in an in vivo mouse model, EFLA 945 attenuates imiquimod (IMQ)-induced psoriasis-related pro-inflammatory responses in topical psoriatic skin, including caspase-1 activation, IL-1β maturation, and IL-17 production, and decreases the severity of psoriasis. Together, these results demonstrate that the safe natural product, EFLA 945, can restrict the AIM2 inflammasome activation through preventing DNA entry and may prove beneficial for treating psoriasis.

  • Cellular cytokine receptor signaling and ATM pathway intersections affect hepatic DNA repair
    Cytokine (IF 3.078) Pub Date : 2019-12-11
    Priya Gupta, Yogeshwar Sharma, Preeti Viswanathan, Sanjeev Gupta
  • Ghrelin alterations during experimental and human sepsis
    Cytokine (IF 3.078) Pub Date : 2019-12-09
    I. Nikitopoulou, E. Kampisiouli, E. Jahaj, A.G. Vassiliou, I. Dimopoulou, Z. Mastora, S. Tsakiris, K. Perreas, M. Tzanela, C. Routsi, S.E. Orfanos, A. Kotanidou

    Background Ghrelin is a hormone mainly produced by cells of the gastric mucosa, which has been shown to possess anti-inflammatory and immunomodulatory properties. The objective of the study was to investigate ghrelin levels during sepsis, as well as in an experimental sepsis model. Methods All consecutive admissions to the ICU of a tertiary hospital in Athens, Greece were screened for eligibility during the study. Thirty four non-septic patients upon ICU admission who subsequently developed sepsis were enrolled. Clinical data and scores were recorded, and blood samples were obtained at baseline (upon ICU admission), and at sepsis development. Total and active ghrelin, leptin, and cytokines were measured. Moreover, lipopolysaccharide (LPS) was administered to mice in order to induce endotoxemia and at specified time points, blood and tissue samples were collected. Results In patients, serum total and active ghrelin concentrations were significantly elevated in sepsis compared to baseline (553.8 ± 213.4 vs 193.5 ± 123.2, p < 0.001; 254.3 ± 70.6 vs 56.49 ± 16.3, p < 0.001). Active ghrelin levels at the sepsis stage were inversely correlated with SOFA score and length of stay in the ICU (p = 0.023 and p = 0.027 respectively). In the mouse endotoxemia model ghrelin levels were elevated following LPS treatment, and the same trend was observed for leptin, TNFα and IL-6. Ghrelin administration managed to reduce IL-6 levels in mouse serum and in BALF. Pulmonary expression of ghrelin and its receptor GHSR1a was found decreased in LPS-treated mice. Conclusions In a well-defined cohort of ICU patients, we have demonstrated that active and total ghrelin increase in sepsis. The same is true for the experimental sepsis model used in the study. The inverse correlation of active ghrelin levels with SOFA score and length of ICU stay among septic patients is indicative of a potential protective role of active ghrelin during the septic process.

  • Cytokine receptor splice variants in hematologic diseases
    Cytokine (IF 3.078) Pub Date : 2019-12-06
    Borwyn Wang, Hrishikesh Mehta

    Cytokine and cytokine receptors are important regulators of hematopoiesis. Hematopoietic stem cells (HSCs) and progenitors differentiate into the myeloid or lymphoid lineage in response to specific cytokines. Cell-type specific receptors are expressed on committed progenitors that bind to other late-acting cytokines that are involved in terminal differentiation of hematopoietic cells. In normal hematopoiesis, these receptors undergo alternative splicing and are developmentally regulated. Splicing changes can significantly affect the structure and function of the receptors resulting in alterations of either the extracellular ligand binding domain or the cytoplasmic signaling domain responsible for cellular growth and differentiation. Most alternatively spliced isoforms generally lose the ability to promote differentiation. Evidently, overexpression of naturally occurring cytokine receptor alternate isoforms are observed in multiple myeloid diseases such as myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and polycythemia vera (PV). The purpose of this review is to introduce the various isoforms of key cytokine receptors that play a crucial role in myeloid development and their potential role in myeloid diseases.

  • Association between polymorphisms of cytokine genes and brucellosis: A comprehensive systematic review and meta-analysis
    Cytokine (IF 3.078) Pub Date : 2019-12-06
    Parisa Zafari, Ahmadreza Zarifian, Reza Alizadeh-Navaei, Mahdi Taghadosi, Alireza Rafiei

    Objective Owing to involvement of host genetic factors in susceptibility to brucellosis infection and its outcome, this study aimed to carry out a comprehensive systematic review and meta-analysis to derive a precise evaluation of the association between the risk of brucellosis and its focal complication and all cytokines examined in case-control studies, including Interferon gamma (IFN-γ), Tumor Necrosis Factor (TNF)-α, TNF-β, Transforming Growth Factor(TGF)-β, IL-2, IL-4, IL-6, IL-10, IL-12B, IL-15, and IL-18 polymorphisms. Methods A systematic literature search in PubMed, Web of Science, Google Scholar, and Scopus was performed to identify the relevant studies, and related information was extracted. The effect size (ES) and corresponding 95% confidence intervals (CIs) were calculated to estimate the association. Results From 158 initial results, twenty-five eligible studies were included in the meta-analysis. Overall, the pooled results showed that the dominant models of IFN-γ UTR5644, TGF-β rs1800470 and rs1800471, TNF-α rs1800629, and IL-10 rs1800872 were significantly less frequent in brucellosis patients than the controls. Also, the pooled analysis of the mutant allele vs. wild allele of TGF-β rs1800471 and IL-10 rs1800872 showed negative association with brucellosis risk. On the other hand, our pooled analysis demonstrated that the mutant allele of IL-4 rs2243250 and IL-18 rs1946519 were associated with increased susceptibility to brucellosis. In addition, the IFN-γ UTR5644 and TGF-β rs1800470 were more frequent in the patients without focal forms. Conclusions IL-4 rs2243250 and IL-18 rs1946519 have a positive correlation with brucellosis whereas the IFN-γ UTR5644, TGF-β rs1800470 and rs1800471, TNF-α rs1800629, and IL-10 rs1800872 showed a negative association with this disease. The association between the other single nucleotide polymorphisms (SNP) and brucellosis risk was not confirmed in the current meta-analysis. PROSPERO Registration: CRD42018117203.

  • Heightened systemic levels of anti-inflammatory cytokines in pulmonary tuberculosis and alterations following anti-tuberculosis treatment
    Cytokine (IF 3.078) Pub Date : 2019-12-04
    Kadar Moideen, Nathella P. Kumar, Ramalingam Bethunaickan, Vaithilingam V. Banurekha, Dina Nair, Subash Babu

    Background Pro-inflammatory cytokines are markers of disease severity and bacterial burden in pulmonary tuberculosis (PTB). However, the association of Type 2, regulatory and other anti-inflammatory cytokines with disease severity and bacterial burden in PTB is not well understood. Aims/methodology To examine the association of anti-inflammatory cytokines with PTB, we examined the plasma levels of Type 2 (IL-4, IL-5, IL-13), regulatory (IL-10, TGFβ) and other anti-inflammatory (IL-19, IL-27, IL-37) cytokines in individuals with PTB, latent TB (LTB) or healthy controls (HC). We also examined the plasma levels of these cytokines in PTB individuals following anti-tuberculosis therapy (ATT). Results PTB individuals exhibited significantly higher plasma levels of IL-4, IL-13, IL-10, IL-19 and IL-27 in comparison to LTB and HC individuals and of TGFβ in comparison to HC individuals. In contrast, PTB individuals exhibited significantly lower plasma levels of IL-5 and IL-37 in comparison to both LTB and HC individuals. PTB individuals with bilateral or cavitary disease did not exhibit significantly different plasma levels of these cytokines in comparison to those with unilateral or non-cavitary disease nor did the cytokines exhibit any significant relationship with bacterial burdens. Finally, following ATT, the plasma levels of IL-4, IL-5 and IL-10 were significantly decreased, while the plasma levels of IL-13 and IL-37 were significantly increased in PTB individuals. Conclusion Therefore, our data demonstrate that PTB is associated with altered levels of Type 2, regulatory and other anti-inflammatory cytokines, some of which are altered followed chemotherapy. Our data also reveal that anti-inflammatory cytokines are not markers of disease severity or bacterial burden in PTB. Elevations in anti-inflammatory cytokines might help prevent the detrimental effects of pro-inflammatory responses in PTB.

  • Adipose tissue dysfunction and metabolic disorders: Is it possible to predict who will develop type 2 diabetes mellitus? Role of markErs in the progreSsion of dIabeteS in obese paTIeNts (The RESISTIN trial)
    Cytokine (IF 3.078) Pub Date : 2019-12-04
    Giuseppe Derosa, Gabriele Catena, Giovanni Gaudio, Angela D'Angelo, Pamela Maffioli

    The aim of this study was to valuate if there are some differences in metabolic parameters among obese which will develop diabetes and those that will not develop diabetes. We enrolled 959 obese, normal glucose tolerant, of either sex, outpatients and evaluated them for 8 years. We evaluated: body mass index (BMI), waist circumference (WC), fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment (HOMA) index, blood pressure, lipid profile, lipoprotein(a), adiponectin (ADN), resistin, leptin, high sensitivity reactive protein (Hs-CRP), tumor necrosis factor-α (TNF-α), retinol binding protein-4 (RBP-4), adipsin, vaspin, visfatin, omentin-1, chemerin. After 8 years of observation, 429 patients maintained euglycemia, while 133 patients developed dysglycemia, and 90 developed diabetes. In dysglycemic patients, ADN was lower, and resistin was higher compared to baseline, while in diabetic patients ADN was lower, and resistin was higher both compared to baseline, and compared to euglycemic and dysglycemic patients. High sensitivity C-reactive protein, TNF-α were higher in both dysglycemic and diabetic patients compared to baseline, but the values recorded in diabetics were higher both compared to euglycemic and dysglycemic. Visfatin was higher and omentin-1 was lower compared to baseline, and compared to euglycemic patients in diabetics. Odds ratio showed that lower levels of adiponectin and higher levels of resistin, but not of other cytokines, increased the risk of developing type 2 diabetes mellitus. Data seem to suggest that lower levels of adiponectin, and higher levels of resistin can be predictive of a future diabetes in obese people, even years before the disease onset.

  • Multiple cytokine analyses of aqueous humor from the patients with retinitis pigmentosa
    Cytokine (IF 3.078) Pub Date : 2019-12-03
    Bing Lu, Houfa Yin, Qiaomei Tang, Wei Wang, Chenqi Luo, Xinyi Chen, Xiaobo Zhang, Kairan Lai, Jingjie Xu, Xiangjun Chen, Ke Yao

    Purpose Cataracts are the most common eye complications of retinitis pigmentosa (RP). This study aimed to investigate the cytokine profiles of the aqueous humor of RP with cataracts. Methods The aqueous humor was collected from RP eyes with cataract (RP group, n = 20) and age-related cataract eyes (ARC group, n = 20) during cataract surgery. The levels of 37 mediators were measured with multiplex fluorescent bead-based immunoassay and compared across groups. The correlation among chemokines, growth factors, and cytokines was analyzed with Spearman’s rank correlation coefficient. Results Twelve cytokines (IL-1α, IL-1β, IL-4, IL-10, TNF-α, IFN-γ, EGF, GM-CSF, PDGF-AB/BB, TGF-α, BMP-9, and E-selection) were below the limit of detection, and the detection rate of IL-6 was significantly higher in RP group than in the ARC group (P < 0.01). Compared with those in the control group, the aqueous humor levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-(IL-)8, interferon gamma-induced protein (IP)-10, hepatocyte growth factor (HGF), platelet-derived growth factor AA (PDGF-AA), matrix metalloproteinase-2 (MMP-2), MMP3, MMP-7, MMP-8, plasminogen activator inhibitor-1 (PAI-1), and thrombospondin-2 (TSP-2) in the RP group increased significantly (P < 0.01). A lower level of BMP-4 in the aqueous humor was observed in the RP patients than in the controls (P < 0.05). Conclusions Significantly increased levels of PDGF-AA, MMP2, MMP3, MMP-7, MMP-8, PAI-1, and TSP-2 and lower levels of BMP-4 were found in the aqueous humor of RP patients. This result indicates a disturbance of the extracellular matrix (ECM) and cytokines in RP patients and suggests a possible role of these cytokines in the pathogenesis of capsular contraction syndrome (CCS) in RP patients.

  • Association of genetic polymorphisms in chromosome 9p21 with risk of ischemic stroke
    Cytokine (IF 3.078) Pub Date : 2019-12-03
    Xuemei Han, Chunhui Wang, Dong Tang, Yuqing Shi, Ming Gao
  • Determination of the cytokine levels in fetal pleural effusion and their association with fetal/neonatal findings
    Cytokine (IF 3.078) Pub Date : 2019-12-02
    Kenji Imai, Tomomi Kotani, Hiroyuki Tsuda, Tomoko Kobayashi, Takafumi Ushida, Yoshinori Moriyama, Fumitaka Kikkawa

    Objectives Few studies have investigated the distribution of multiple cytokines in fetal pleural effusion, and its clinical implications are uncertain. This study aimed to determine cytokine levels in fetal pleural effusion and their clinical role in affected fetuses. Methods We obtained fetal pleural fluid samples from 18 infants and investigated the profiles of 40 cytokines using multiplex immunoassay. Relationships among cytokines were estimated by Spearman correlation analysis. Possible associations of cytokine levels with fetal adverse outcomes, including perinatal demise and neurodevelopmental impairment, were studied using univariate logistic regression analysis. Results Several pro-inflammatory cytokines and CCL chemokines were highly correlated with each other. In contrast, CXCL chemokines had relatively weak correlations with other cytokines. The levels of IL-1β, IL-2, and CCL20 were significantly associated with the occurrence of fetal adverse outcomes. Based on our findings, IL-1β had the strongest causal link to adverse outcomes among the cytokines [odds ratio (OR): 19.74; 95% confidence interval (CI): 1.14–341.9; p = 0.040]. Conclusions Cytokine levels in fetal pleural effusion varied considerably among cases with or without adverse outcomes. These results provide important information for further clarifying the pathophysiology of fetal pleural effusion and a novel clinical implication that could predict the occurrence of adverse outcomes.

  • PEGylation of a glycosaminoglycan-binding, dominant-negative CXCL8 mutant retains bioactivity in vitro and in vivo
    Cytokine (IF 3.078) Pub Date : 2019-11-30
    T. Gerlza, C. Trojacher, D. Jeremic, E. Krieger, T. Adage, A. Kungl

    We have recently shown that a dominant-negative mutant of CXCL8, dnCXCL8, with increased glycosaminoglycan (GAG) binding affinity and inactivated GPCR signaling function is able to efficiently prevent neutrophil infiltration into murine lungs (Adage et al., 2015). Here we present evidence that chemical PEGylation of dnCXCL8 with 20 kDa and 40 kDa PEG does not significantly interfere with GAG binding affinity, nor does it influence the mutant’s disabled chemotaxis function, while it strongly improved bioavailability and serum half-life of the chemokine mutant. In a murine model of lung inflammation, only the 40 kDa PEGylated dnCXCL8 showed a significant reduction of neutrophils in bronchoalveolar lavage (BAL) fluid. In combination with an almost three-fold increase (compared to non-PEGylated dnCXCL8) in plasma half-life after intravenous administration, our results prove that PEGylation of chemokine-derived biologics is an amenable way for the treatment of chronic inflammatory conditions.

  • Who’s in charge here? Macrophage colony stimulating factor and granulocyte macrophage colony stimulating factor: Competing factors in macrophage polarization
    Cytokine (IF 3.078) Pub Date : 2019-11-28
    Evan Trus, Sameh Basta, Katrina Gee

    Macrophages make up a crucial aspect of the immune system, carrying out a variety of functions ranging from clearing cellular debris to their well-recognized roles as innate immune cells. These cells exist along a spectrum of phenotypes but can be generally divided into proinflammatory (M1) and anti-inflammatory (M2) groups, representing different states of polarization. Due to their diverse functions, macrophages are implicated in a variety of diseases such as atherosclerosis, lupus nephritis, or infection with HIV. Throughout their lifetime, macrophages can be influenced by a wide variety of signals that influence their polarization states, which can affect their function and influence their effects on disease progression. This review seeks to provide a summary of how GM-CSF and M-CSF influence macrophage activity during disease, and provide examples of in vitro research that indicate competition between the two cytokines in governing macrophage polarization. Gaining a greater understanding of the relationship between GM-CSF and M-CSF, along with how these cytokines fit into the larger context of diseases, will inform their use as treatments or targets for treatment in various diseases.

  • 更新日期:2019-11-29
  • IL-27 is elevated in sepsis with acute hepatic injury and promotes hepatic damage and inflammation in the CLP model
    Cytokine (IF 3.078) Pub Date : 2019-11-28
    Jing Fan, Yu-chi Zhang, Dao-feng Zheng, Mu Zhang, Hang Liu, Miao He, Zhong-jun Wu

    Background Immuno-inflammation plays an important role in the pathophysiological process of sepsis-associated acute hepatic injury (AHI). Interleukin 27 (IL-27) is an important inflammatory regulator; however, its role in this condition is not clear. Methods The clinical data and IL-27 serum levels in sepsis patients with or without AHI were analysed. Classical caecal ligation puncture (CLP) models were established in wild-type (WT) and IL-27 receptor (WSX-1)-deficient (IL-27R−/−) mice. In addition, exogenous IL-27 was injected into these mice, and the levels of IL-27, IL-6, and tumour necrosis factor alpha (TNF-α) in the serum and liver were then measured by enzyme-linked immunoassay (ELISA), quantitative PCR, and Western blotting. The severity of liver damage was evaluated by haematoxylin and eosin staining of liver tissue, TUNEL assay and evaluation of alanine aminotransferase (ALT) and aspartate transaminase (AST) serum levels. Furthermore, the effects of IL-27 on the levels of phosphorylated c-Jun N-terminal kinase (JNK) in macrophages were assessed by Western blotting, and the effects of IL-27 on the expression of IL-6 and TNF-α in macrophages were assessed by ELISA. Results IL-27 was elevated in sepsis patients with acute hepatic injury, which correlated with the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHEII) scores, Sequential Organ Failure Assessment (SOFA) scores, and procalcitonin, C-reactive protein, IL-6, and TNF-α expression. In the CLP-WT group, IL-27 was highly expressed in the serum and liver, which correlated with the elevated content of ALT, AST, TNF-α, IL-6, and p-JNK in the serum and liver and the pathological injury of the liver. In CLP-IL-27R−/− group, however, the levels of ALT, AST, TNF-α, IL-6, and p-JNK in the serum and liver and the pathological injury of the liver were decreased. Treatment with exogenous IL-27 led to a further increase in these cytokines in WT mice after CLP. IL-27 treatment and lipopolysaccharide stimulation in vitro increased the expression of p-JNK, IL-6, and TNF-α in macrophages, and these changes were decreased by a JNK signalling pathway inhibitor. Conclusion IL-27 is elevated in sepsis patients, especially those with acute hepatic injury. In addition, IL-27 can promote inflammatory reactions in the CLP-induced hepatic injury mice model.

  • Immunohistochemical staining with chemokine panel of non-specific colitis predicts future IBD diagnosis
    Cytokine (IF 3.078) Pub Date : 2019-11-27
    Aymen M. El-Saka, Yomna A. Zamzam, Tamer Haydara, Sherief Abd-Elsalam

    Background & aims There is a possible significant difficulty in differentiating between non-specific colitis (NSC) and early IBD patients with no cardinal endoscopic features. This clarifies the need to find markers with high sensitivity and specificity for distinguishing between both and other forms of specific colitis. The aim of this study to investigate the ability to use a chemokine panel (CCR9, CD146 and Foxp3) among patients with lower gastrointestinal symptoms found to have NSC (but do not have current IBD) to predict which patients progress to/develop future IBD or other diagnoses of specific colitis. Methods Colonoscopy was done for 182 patients complaining of chronic diarrhea and or constipation, abdominal distention and pain with negative history for IBD, after Histopathological evaluation; 138 cases showing non-specific inflammation submitted for further immunohistochemical CCR9, CD146 and Foxp3 staining. On follow up patients with persistent symptoms or worsen symptoms recolonoscopy was done followed by Histopathological examination of samples and compared by the earlier results. Results The studied markers expressed significantly in IBD patients differentiating them from NSC patients (p < 0.001) except for CCR9 expression was statistically insignificant in CD patients (p = 0.528). According to the ROC curves in prediction of progression using studied panel, the use of studied markers in combination was more statistically significant in comparison to each marker alone. Median follow up for studied patients was 12 months. Conclusions This panel of markers holds a promising hope for early IBD as predictive markers, discriminating IBD from NSC and as potential therapeutic targets.

  • Interleukin 2 regulates the activation of human basophils
    Cytokine (IF 3.078) Pub Date : 2019-11-26
    Shuli Zhao, Yangyang Tang, Li Hong, Meizhen Xu, Shuai Pan, Kuiyang Zhen, Renxian Tang, Xiaoxiang Zhai, Zhixu Shi, Hui Wang

    Basophils are important effector cells in allergic disorders and anti-parasitic immune response. A number of activators including interleukin 3 (IL-3) and IgE have been identified in the regulation of human basophils expressing mediators such as histamine and leukotriene C4 (LTC4) and cytokines, including IL-4 and IL-13. Human basophils express high levels of IL-2 receptors. However, the function of the IL-2 pathway in basophils remains unknown. Here, we identified that IL-2 induced the activation of human basophils in vitro to express a variety of inflammatory cytokines and chemokines including IL-5, IL-13, GM-CSF and CCL-17. This effect by IL-2 is confirmed by an upstream regulator analysis using Ingenuity pathway analysis. Of note, one of the top regulated cytokines, IL-5, was for the first time identified to be induced by IL-2 in human basophils rather than IL-3 or anti-IgE. Immunofluorescence analysis of skin specimens from bullous pemphigoid and eczema revealed that infiltrating basophils in skin lesions widely expressed IL-5 and GM-CSF. Together, our findings reveal IL-2 as a novel regulator of human basophils. This adds a new layer to support the importance of basophils in allergic disorders.

  • ANRIL polymorphisms (rs1333049 and rs3217992) in relation to plasma CRP levels among in-patients with CHD
    Cytokine (IF 3.078) Pub Date : 2019-11-27
    Stefan Reichert, Linda Seitter, Hans-Günter Schaller, Axel Schlitt, Susanne Schulz

    Background Single nucleotide polymorphisms (SNPs) in long non-coding RNA ANRIL (antisense noncoding RNA in the INK4 locus) were shown to be associated with coronary heart disease (CHD). The biological background for this association is not fully understood. The primary aim of this study was to investigate whether two leading ANRIL SNPs, namely, rs133049 and rs3217992, were associated with plasma levels of C-reactive protein among a large cohort of in-patients with CHD (n = 933). Material and methods CHD was defined as previous or current detection of 50% stenosis of a main coronary artery. Severe periodontitis was diagnosed if proximal attachment loss of at least 5 mm was found in at least 30% of teeth. For genotyping rs1333049 we applied PCR using sequence-specific primers and for rs321799 restriction fragment length polymorphism analyses. C-reactive protein (CRP) plasma levels were determined using a particle-enhanced immunological turbidity test. In addition, interleukin (IL)-6, low-density lipoprotein (LDL), total cholesterol, high-density lipoprotein (HDL), triglycerides, and number of leukocytes were determined. Results Genotype CC of rs1333049 was significantly associated with both elevated CRP levels and decreased HDL concentrations after univariate (p = 0.028, p = 0.012) and multivariate analysis (p = 0.041, p = 0.023) stratified for age, gender, body mass index, smoking, diabetes, and severe periodontitis. Furthermore, severe periodontitis (p = 0.031), but not SNP rs3217992, was associated with CRP plasma concentrations. Conclusions Among patients with CHD, ANRIL SNP rs1333049 is an independent risk indicator for both elevated CRP plasma levels and reduced HDL concentrations. ClinicalTrials.gov Identifier: NCT01045070.

  • Strongyloides venezuelensis-infection alters the profile of cytokines and liver inflammation in mice co-infected with Schistosoma mansoni
    Cytokine (IF 3.078) Pub Date : 2019-11-26
    Michelle Carvalho de Rezende, João Marcelo Peixoto Moreira, Laura Liana Maggi Fernandes, Vanessa Fernandes Rodrigues, Deborah Negrão-Corrêa

    Human co-infection by helminth species is frequent, but their consequences are mostly unknown. Here, we investigate the impact of Strongyloides venezuelensis co-infection on the immune response, schistosome burden, and the associated pathology of schistosomiasis in mice. Co-infection did not alter the schistosome parasite burden, but reduced the IL-4/IL-10 ratio during acute schistosomiasis, indicating induction of modulatory mechanisms. Simultaneous infection with S. venezuelensis and S. mansoni increased the liver concentration of IFN-γ and altered the Th2/Th1 balance, leading to great infiltration of neutrophils and macrophages, which resulted in larger liver inflammation and increased serum transaminase activity in comparison with mono-infected mice. Mice infected with S. venezuelensis at two and four weeks after S. mansoni infection showed significant increase of Th1/Th2/Th17/Treg cytokines and strong cellular infiltration in the liver in comparison with mono-infected mice. However, only in mice co-infected after two weeks of schistosomiasis, the liver immune response leads to more intense Th2 polarization, increased liver inflammation, and transaminase serum activity. S. venezuelensis co-infection during chronic schistosomiasis did not significantly alter liver inflammation. Therefore, S. venezuelensis co-infection affects the host immune responses and morbidity of schistosomiasis, but the effects largely depend on the stage of the S. mansoni infection.

  • Protective effect of triterpenes of Ganoderma lucidum on lipopolysaccharide-induced inflammatory responses and acute liver injury
    Cytokine (IF 3.078) Pub Date : 2019-11-24
    Zhongpeng Hu, Ruiping Du, Lei Xiu, Ziyao Bian, Chaomei Ma, Naoto Sato, Masao Hattori, Haochi Zhang, Yanchen Liang, Shuixing Yu, Xiao Wang
  • Increased systemic inflammation in children with Down syndrome
    Cytokine (IF 3.078) Pub Date : 2019-11-27
    Dean Huggard, Lynne Kelly, Emer Ryan, Fiona McGrane, Niamh Lagan, Edna Roche, Joanne Balfe, T. Ronan Leahy, Orla Franklin, Derek G. Doherty, Eleanor J. Molloy

    Children with Down syndrome (DS) develop more infections, have an increased mortality from sepsis and an increased incidence of chronic inflammatory conditions. Cytokine dysregulation may underpin these clinical sequelae and raised pro-inflammatory biomarkers are a feature in adults with DS. The importance of the anti-inflammatory mediators IL-1ra and IL-10, as well as cytokines Epo and VEGF, which could impact on the pathogenesis and outcomes in congenital heart disease (CHD) which is more prevalent in DS, are less well known. We examined a comprehensive array of pro-(IL-2, IL-6, IL-8, IL-18, IL-1β, TNF-α, IFN-γ), and anti-inflammatory (IL-10 and IL-1ra) mediators, cytokines involved in inflammation in response to hypoxia (EPO), propagating angiogenesis (VEGF), and myelopoiesis (GM-CSF), by enzyme linked immunosorbent assay (ELISA), as well as discussing the potential impact of significant CHD and Lipopolysaccharide endotoxin on these mediators. 114 children with DS and 60 age and sex matched controls were recruited. Children with Down syndrome exhibit significantly greater levels of pro and anti-inflammatory cytokines; IL-2, IL-6, IL-10, IL-1ra, as well as increased Epo, VEGF and GM-CSF at baseline. CHD does not seem to have an impact on circulating cytokines beyond the acute surgical phase. Both cohorts had similar responses to LPS stimulation. These differences may contribute to varied clinical outcomes, acutely like in sepsis, and over time in autoimmunity.

  • Preliminary observation of chemokine expression in patients with Stanford type A aortic dissection
    Cytokine (IF 3.078) Pub Date : 2019-11-28
    Fudong Fan, Qing Zhou, Jun Pan, Qiang Wang, Hailong Cao, Yunxing Xue, Zhenjun Xu, Dongjin Wang

    Stanford type A Aortic dissection (TAAD) is a deadly cardiovascular disease but the relationship between inflammatory cytokines and disease pathogenesis is still unclear. Observation of the changes of different chemokines may help to explore the etiology of TAAD much further. Clinical data was collected from TAAD patients (TAAD group) and healthy controls (HC group) in our institute between October 2013 and December 2014. Blood sample was harvested from each subject of two groups. The expression levels of eighty chemokines were examined by protein array technology. Then we tested the expressions of macrophage inflammatory protein 1β (MIP-1β), epithelial neutrophil activating peptide 78 (ENA-78), interleukin 16 (IL-16), interferon inducible protein 10 (IP-10), and FMS-like tyrosine kinase 3 (Flt-3) ligand by using luminex technology. Osteopontin (OPN) and monocyte chemotaxis protein (MCP) levels were analyzed by ELISA kits. The mean age of TAAD group is 49.9 ± 11.2 and 48.7 ± 9.9 in HC group, respectively. 76.0% of TAAD patients and 72.0% of healthy controls were male. MIP-1β and ENA-78 expression in TAAD group were significantly lower than that in HC group, while significant increasing IL-16 level was found. Plasma levels of OPN in TAAD group increased remarkably compared with HC group, but MCP-1 and MCP-2 expression significantly decreased. No correlation was shown between serum CRP levels and plasma level of these cytokines by using Spearman analysis. ROC analysis showed that OPN could be indicators for TAAD diagnosis with sensitivity of 0.92 and specificity of 0.99. Our results provide a reasonable way to focus on the chemokines in understanding the pathogenesis of human TAAD.

  • Pro-inflammatory cytokines associate with NETosis during sickle cell vaso-occlusive crises
    Cytokine (IF 3.078) Pub Date : 2019-11-25
    Emilia A Barbu, Laurel Mendelsohn, Leigh Samsel, Swee Lay Thein

    Recurring episodes of acute pain, also referred to as vaso-occlusive crises (VOC), are characteristic of sickle cell disease (SCD), during which pro-inflammatory cytokines, chemokines, adhesion markers and white cell count, some already elevated at steady state, increase further. Hydroxyurea (HU) is licensed by the FDA for reducing frequency of VOCs in SCD; increased fetal hemoglobin (HbF) together with reduction of the neutrophil count and circulating inflammatory markers, contribute to its clinical efficacy. Here, using paired plasma samples from HbSS patients (in steady-state and VOC) we determined that despite HU treatment, the SCD environment remained highly inflammatory and particularly at VOC, triggered neutrophil activity. While neutrophil extracellular traps (NETs) induction by the steady state plasmas were comparable to that of plasma from healthy donors, the NETs response triggered by crisis plasmas was significantly increased over that of the steady state (P = 0.0124*). Levels of IL-6 and IL-1α, IL-1ra/IL1F3 and adhesion molecule P-selectin were significantly increased in the VOC plasma when compared with steady state plasma. Higher levels of IL-6 and IL-1ra were also found in the crises samples that yielded an increased NETs response suggesting that increased NETs production associated with increased levels of the inflammatory products of the IL-6 family and regulators of IL-1 family of cytokines during sickle VOCs.

  • Circulating concentration of interleukin-37 in Helicobacter pylori-infected patients with peptic ulcer: Its association with IL-37 related gene polymorphisms and bacterial virulence factor CagA
    Cytokine (IF 3.078) Pub Date : 2019-11-19
    Elham Davarpanah, Abdollah Jafarzadeh, Maryam Nemati, Arezoo Bassagh, Mehdi Hayatbakhsh Abasi, Arezu Khosravimashizi, Nadia Kazemipoor, Motahareh Ghazizadeh, Moghaddameh Mirzaee

    The immunopathologic responses play a major role in the development of H. pylori (HP)-related gastrointestinal diseases. IL-37 is an anti-inflammatory cytokine with potent suppressive effects on innate and adaptive immune responses. Here, we investigated the IL-37 levels and two single nucleotide polymorphisms (SNPs) including rs3811047 and rs2723176 in IL-37 gene in HP-infected peptic ulcer (PU) patients to identify any relationship. Three groups, including 100 HP-infected PU patients, 100 HP-infected asymptomatic (AS) subjects and 100 non-infected healthy control (NHC) subjects were enrolled to study. Serum IL-37 levels and the genotyping at rs3811047 and rs2723176 were determined using ELISA and SSP–PCR methods, respectively. Significantly higher IL-37 levels were observed in PU patients compared with AS and NHC groups (P < 0.0001). In both PU and AS groups, the CagA+ HP-infected participants displayed higher IL-37 levels compared with those infected with CagA− strains (P < 0.0001). There were significant differences between PU, AS and NHC groups regarding the distribution of genotypes and alleles at rs3811047 and rs2723176 SNPs. The genotype GG and allele G at IL-37 rs3811047 SNP, and the genotype CC and allele C at IL-37 rs2723176 SNP more frequently expressed in PU patients than total healthy subjects (AS + NHC groups) and were associated with an increased risk of PU development (genotype GG: RR = 3.08, P < 0.009; allele G: RR = 2.94, P < 0.01; genotype CC: RR = 5, P < 0.01; and allele C: RR = 5.0, P < 0.02, respectively). The PU patients with allele A at IL-37 rs2723176 SNP expressed higher amounts of IL-37 compared with patients carried allele C at the same position (P < 0.05). In AS carriers and NHC individuals, the IL-37 levels in subjects carried genotype AA or allele A at IL-37 rs2723176 SNP were higher than those carried genotype CC or allele C at the same location (P < 0.01 and P < 0.02 for AS group; P < 0.0001 and P < 0.001 for NHC subjects, respectively). The increased IL-37 levels may be considered as a valuable marker of PU development in HP-infected individuals. The SNPs rs3811047 and rs2723176 were associated with PU development. The CagA status of HP and IL-37 rs2723176 SNP may affect the IL-37 levels.

  • Effect of flaxseed supplementation on markers of inflammation and endothelial function: A systematic review and meta-analysis
    Cytokine (IF 3.078) Pub Date : 2019-11-15
    Moein Askarpour, Mohammadreza Karimi, Amir Hadi, Ehsan Ghaedi, Micheal E. Symonds, Maryam Miraghajani, Parisa Javadian

    Objectives The rationale for the current study was to evaluate the efficacy of flaxseed supplementation on important adhesion molecules and inflammatory cytokines in adults. Methods We conducted searches of published literature in PubMed, Scopus, Web of Science, and Google Scholar databases from inception until May 2019. All randomized controlled trials (RCTs) which investigated the effects of flaxseed supplementation on the circulating concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), vascular cell adhesion protein 1 (VCAM-1), E-selectin, and intercellular adhesion molecule 1 (ICAM-1) were included in our analysis. Results were summarized using weighted mean differences (WMDs) by random-effects model. Results Forty eligible RCTs, including 2520 participants were identified. The results of the meta‐analysis revealed flaxseed supplementation reduced the concentrations of CRP (WMD = −0.387 mg/L; 95% CI: −0.653, −0.121, p = 0.004), IL-6 (WMD = −0.154 pg/Ml; 95% CI: −0.299, −0.010, p = 0.036), and VCAM-1 (WMD = –22.809 ng/ml; 95% CI: −41.498, −4.120, p = 0.017) but had no significant effect on TNF-α (WMD = -0.077 pg/mL; 95% CI: −0.317, 0.163, p = 0.530), ICAM-1 (WMD = −8.610 ng/ml; 95% CI: −21.936, 4.716, p = 0.205), and E-selectin (WMD = −1.427 ng/ml; 95% CI: −4.074, 1.22, p = 0.291). Conclusions These findings showed that flaxseed supplementation may improve some circulating concentrations of specific adhesion molecules and inflammatory cytokines. However, well-designed trials are needed to confirm the range of non-significant and/or equivocal findings.

  • Platelet-derived alpha-granules are associated with inflammation in patients with NK/T-cell lymphoma-associated hemophagocytic syndrome
    Cytokine (IF 3.078) Pub Date : 2019-11-15
    Quanguang Ren, Ka-wo Chan, He Huang, Zhao Wang, Xiaojie Fang, Chengcheng Guo, Fangfang Li, Limei Zhang, Yuyi Yao, Zegeng Chen, Ying Tian, Tongyu Lin

    Due to the variable overlap of multiple symptoms, accurate early diagnosis of NK/T-cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS) is difficult, making the prognosis extremely poor. Hemophagocytic syndrome (HPS) is now diagnosed primarily based on the hemophagocytic lymphohistiocytosis (HLH)-2004 diagnostic criteria, and platelet count is one of the baseline evaluations. However, in our study, the data showed that decreased platelets were not only a clinical feature of HPS but also the key cells that regulate inflammation by releasing α-granules containing upregulated platelet factor 4 (PF4) and downregulated platelet-derived growth factors (PDGFs). Furthermore, we found that angiopoietin-4 (ANG-4), which has significant differential expression, has been less reported, that may affect hematopoiesis and proinflammatory responses and can be used as diagnostic biomarkers together with PF4 and PDGFs.

  • Chemokine (C-C motif) ligand 2 and coronary artery disease: Tissue expression of functional and atypical receptors
    Cytokine (IF 3.078) Pub Date : 2019-11-15
    Anna Hernández-Aguilera, Montserrat Fibla, Noemí Cabré, Fedra Luciano-Mateo, Jordi Camps, Salvador Fernández-Arroyo, Vicente Martín-Paredero, Javier A. Menendez, Juan J. Sirvent, Jorge Joven

    Chemokines, particularly chemokine (C-C- motif) ligand 2 (CCL2), control leukocyte migration into the wall of the artery and regulate the traffic of inflammatory cells. CCL2 is bound to functional receptors (CCR2), but also to atypical chemokine receptors (ACKRs), which do not induce cell migration but can modify chemokine gradients. Whether atherosclerosis alters CCL2 function by influencing the expression of these receptors remains unknown. In a necropsy study, we used immunohistochemistry to explore where and to what extent CCL2 and related receptors are present in diseased arteries that caused the death of men with coronary artery disease compared with unaffected arteries. CCL2 was marginally detected in normal arteries but was more frequently found in the intima. The expression of CCL2 and related receptors was significantly increased in diseased arteries with relative differences among the artery layers. The highest relative increases were those of CCL2 and ACKR1. CCL2 expression was associated with a significant predictive value of atherosclerosis. Findings suggest the need for further insight into receptor specificity or activity and the interplay among chemokines. CCL2-associated conventional and atypical receptors are overexpressed in atherosclerotic arteries, and these may suggest new potential therapeutic targets to locally modify the overall anti-inflammatory response.

  • TREX1 variants in Sjogren's syndrome related lymphomagenesis
    Cytokine (IF 3.078) Pub Date : 2019-07-18
    Adrianos Nezos, Panagiota Makri, Saviana Gandolfo, Salvatore De Vita, Michael Voulgarelis, Mary K. Crow, Clio P Mavragani

    Genetic variants of the three-prime repair exonuclease 1 (TREX1) -an exonuclease involved in DNA repair and degradation- have been previously found to increase susceptibility to Aicardi Goutieres syndrome, familial chilblain lupus and systemic lupus erythematosus. We aimed to explore whether TREX1 common variants could influence the risk of primary Sjogren’s syndrome (SS) and SS-related lymphoma. Three single nucleotide polymorphisms (SNPs) of the TREX1 gene (rs11797, rs3135941 and rs3135945) were evaluated in 229 SS, 89 SS-lymphoma (70 SS-MALT and 19 SS non-MALT) and 240 healthy controls by PCR-based assays. In available 52 peripheral blood and 26 minor salivary gland tissues from our SS cohort, mRNA expression of type I interferon (IFN) related genes and TREX1 was determined by real-time PCR. Significantly decreased prevalence of rs11797 A minor allele was detected in SS patients complicated by non-MALT lymphoma compared to controls (ΟR [95% CI]: 0.4 [0.2–0.9], p-value: 0.02). SS patients carrying the rs11797 AA genotype had increased type I IFN related gene mRNA expression in minor salivary gland tissues. These data support genetically related dampened type I IFN production as an additional mechanism for SS-related lymphomagenesis.

  • Bone marrow mesenchymal stem cells from patients with SLE maintain an interferon signature during in vitro culture
    Cytokine (IF 3.078) Pub Date : 2019-05-29
    Lin Gao, Mary OConnell, Maria Allen, Jane Liesveld, Andrew McDavid, Jennifer H. Anolik, Richard J. Looney

    Background We have previously shown that SLE BMSC have decreased proliferation, increased ROS, increased DNA damage and repair (DDR), a senescence associated secretory phenotype, and increased senescence-associated β-galactosidase. We have also shown SLE BMSC produce increased amounts of interferon beta (IFNβ), have increased mRNA for several genes induced by IFNβ, and have a pro-inflammatory feedback loop mediated by a MAVS. To better understand the phenotype of SLE BMSC we conducted mRNA sequencing. Methods Patients fulfilling SLE classification criteria and age and sex matched healthy controls were recruited under an Institutional Review Board approved protocol. Bone marrow aspirates and peripheral blood samples were obtained. BMSC were isolated and grown in tissue culture. Early passage BMSC were harvested and mRNA samples were sent for RNAseq. Serum samples were assayed for IFNβ by ELISA. Results On the basis of top differentially expressed genes between SLE and healthy controls, SLE patients with high levels of serum IFNβ clustered together while SLE patients with low levels of IFNβ clustered with healthy controls. Those genes differentially expressed in SLE patients generally belonged to known IFN pathways, and showed a strong overlap with the set of genes differentially expressed in IFNβ high subjects, per se. Moreover, gene expression changes induced by treating healthy BMSC with exogenous IFNβ were remarkably similar to gene expression differences in SLE IFNβ high vs low BMSC. Conclusions BMSCs from SLE patients are heterogeneous. A subgroup of SLE BMSC is distinguished from other SLE BMSC and from controls by increased levels of mRNAs induced by type I interferons. This subgroup of SLE patients had increased levels of IFNβ in vivo.

  • Coordination between innate immune cells, type I IFNs and IRF5 drives SLE pathogenesis
    Cytokine (IF 3.078) Pub Date : 2019-05-23
    Bharati Matta, Betsy J. Barnes

    Systemic lupus erythematosus (SLE) is a complex autoimmune disease which affects multiple organs. The type I interferon (IFN) gene signature and circulating autoantibodies are hallmarks of SLE. Plasmacytoid dendritic cells (pDCs) are considered the main producers of type I IFN and production is modulated by multiple other immune cell types. In SLE, essentially every immune cell type is dysregulated and aberrant deregulation is thought to be due, in part, to direct or indirect exposure to IFN. Genetic variants within or around the transcription factor interferon regulatory factor 5 (IRF5) associate with SLE risk. Elevated IFNα activity was detected in the sera of SLE patients carrying IRF5 risk polymorphisms who were positive for either anti-RNA binding protein (anti-RBP) or anti-double-stranded DNA (anti-dsDNA) autoantibodies. Neutrophils are also an important source of type I IFNs and are found in abundance in human blood. Neutrophil extracellular traps (NETs) are considered a potential source of antigenic trigger in SLE that can lead to type I IFN gene induction, as well as increased autoantibody production. In this review, we will focus on immune cell types that produce type I IFNs and/or are affected by type I IFN in SLE. In addition, we will discuss potential inducers of endogenous type I IFN production in SLE. Last, we will postulate how the different immune cell populations may be affected by an IRF5-SLE risk haplotype.

  • Interferon (IFN)-inducible Absent in Melanoma 2 proteins in the negative regulation of the type I IFN response: Implications for lupus nephritis
    Cytokine (IF 3.078) Pub Date : 2019-03-20
    Divaker Choubey, Ravichandran Panchanathan

    Systemic lupus erythematosus (SLE) is a complex autoimmune disease that exhibits a strong female bias (female-to-male ratio 9:1) in patients. Further, 40–60% SLE patients develop lupus nephritis (LN), which significantly increases the mortality rates. The failure of current therapies to adequately treat LN in patients reflects an incomplete understanding of the disease pathogenesis. Notably, a chronic increase in serum interferon-α (IFN-α) activity is a heritable risk factor to develop SLE. Accordingly, blood cells from most SLE patients with an active disease exhibit an increase in the expression of the type I IFN (IFN-α/β)-stimulated genes (ISGs, also referred to as “IFN-signature”), a type I IFN response. Further, LN patients during renal flares also exhibit an “IFN-signature” in renal biopsies. Therefore, an improved understanding of the regulation of type I IFNs expression is needed. Basal levels of the IFN-β through “priming” of IFN-α producing cells augment the expression of the IFN-α genes. Of interest, recent studies have indicated a role for the type I IFN-inducible Absent in Melanoma 2 proteins (the murine Aim2 and human AIM2) in the negative regulation of the type I IFN response through inflammasome-dependent and independent mechanisms. Further, an increase in the expression of Aim2 and AIM2 proteins in kidney and renal macrophages associated with the development of nephritis. Therefore, we discuss the role of Aim2/AIM2 proteins in the regulation of type I IFNs and LN. An improved understanding of the mechanisms by which the Absent in Melanoma 2 proteins suppress the type I IFN response and modulate nephritis is key to identify novel therapeutic targets to treat a group of LN patients.

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上海纽约大学William Glover