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  • Human Papillomavirus and carcinogenesis: Novel mechanisms of cell communication involving extracellular vesicles
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2020-01-18
    Maria Vincenza Chiantore; Giorgio Mangino; Marco Iuliano; Lorena Capriotti; Paola Di Bonito; Gianna Fiorucci; Giovanna Romeo

    A small group of mucosal Human Papillomaviruses are the causative agents of cervical cancer and are also associated with other types of cancers. Certain cutaneous Human Papillomaviruses seem to have a role as co-factors in the UV-induced carcinogenesis of the skin. The main mechanism of the tumorigenesis induced by Human Papillomaviruses is linked to the transforming activity of the viral E6 and E7 oncoproteins. However, other mechanisms, such as the gene expression control by specific microRNAs expression and deregulation of immune inflammatory mediators, may be important in the process of transformation. In this context, the release of Extracellular Vesicles with a specific cargo (microRNAs involved in tumorigenesis, mRNAs of viral oncoproteins, cytokines, chemokines) appears to play a key role.

  • 更新日期:2020-01-13
  • Microvesicles and exosomes in metabolic diseases and inflammation
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2020-01-03
    L Dini; S. Tacconi; E. Carata; A.M. Tata; C. Vergallo; E. Panzarini
  • Tumor-derived extracellular vesicles and microRNAs: Functional roles, diagnostic, prognostic and therapeutic options
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-12-31
    Giada Pontecorvi; Maria Bellenghi; Rossella Puglisi; Alessandra Carè; Gianfranco Mattia
  • Large Extracellular vesicles: Size matters in tumor progression
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-12-31
    Chiara Ciardiello; Rossella Migliorino; Alessandra Leone; Alfredo Budillon
  • Extracellular vesicle-mediated intercellular communication in HIV-1 infection and its role in the reservoir maintenance
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-12-27
    Eleonora Olivetta; Chiara Chiozzini; Claudia Arenaccio; Francesco Manfredi; Flavia Ferrantelli; Maurizio Federico

    HIV-1 infection is efficiently controlled by combination anti-retroviral therapy (cART). However, despite preventing disease progression, cART does not eradicate virus infection which persists in a latent form for an individual’s lifetime. The latent reservoir comprises memory CD4+ T lymphocytes, macrophages, and dendritic cells; however, for the most part, the reservoir is generated by virus entry into activated CD4+ T lymphocytes committed to return to a resting state, even though resting CD4+ T lymphocytes can be latently infected as well. The HIV-1 reservoir is not recognized by the immune system, is quite stable, and has the potential to re-seed systemic viremia upon cART interruption. Viral rebound can occur even after a long period of cART interruption. This event is most likely a consequence of the extended half-life of the HIV-1 reservoir, the maintenance of which is not clearly understood. Several recent studies have identified extracellular vesicles (EVs) as a driving force contributing to HIV-1 reservoir preservation. In this review, we discuss recent findings in the field of EV/HIV-1 interplay, and then propose a mechanism through which EVs may contribute to HIV-1 persistence despite cART. Understanding the basis of the HIV-1 reservoir maintenance continues to be a matter of great relevance in view of the limitations of current strategies aimed at HIV-1 eradication.

  • Functions of FGFR2 corrupted by translocations in intrahepatic cholangiocarcinoma
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-12-19
    Fangda Li; Malalage N. Peiris; Daniel J. Donoghue

    Cholangiocarcinoma, originating from the biliary duct, represents a subset of liver cancer. With about 8,000 new cases of cholangiocarcinoma diagnosed annually in the U.S., these fall into three categories: intrahepatic, peri-hilar, and extrahepatic cholangiocarcinoma. Arising from the epithelium of the bile duct, intrahepatic cholangiocarcinoma (ICC) is a universally fatal malignancy with very few treatment options. The poor prognosis and lack of molecular targeted therapies highlights ICC as a critical unmet medical need. With advances in sequencing technology, numerous chromosomal translocations have been discovered as drivers in cancer initiation and progression. Particularly in ICC, chromosomal translocations involving Fibroblast Growth Factor Receptor 2 (FGFR2) have been frequently identified, resulting in the creation of oncogenic fusion proteins. At the N-terminus, these fusion proteins share a nearly-identical FGFR2 moiety retaining an intact kinase domain and, at the C-terminus, a dimerization/oligomerization domain provided by different partner genes, including: Periphilin 1 (PPHLN1), Bicaudal family RNA binding protein 1 (BICC1), Adenosylhomocysteinase Like 1 (AHCYL1), and Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3). A number of pre-clinical and clinical trials have shown the effectiveness of FGFR inhibitors in treating FGFR2 fusion-positive ICC patients. However, the efficacy of these inhibitors may be short-lived due to acquired resistance. In this review, we provide an overview of FGFR2 fusions, comparing their structures and mechanism of dimerization, examining the importance of FGFR2 as a partner gene, as well as highlighting the significance of alternative splicing of FGFR2 in these fusion proteins. In addition, we discuss various therapeutic options and their associated potencies in targeting these translocation-induced ICCs.

  • An emerging interplay between extracellular vesicles and cytokines
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-12-18
    Alessandra Aiello; Flavia Giannessi; Zulema A. Percario; Eisabetta Affabris

    Extracellular vesicles (EVs) are small membrane-bound particles that are naturally released from cells. They are recognized as potent vehicles of intercellular communication both in prokaryotes and eukaryotes. Because of their capacity to carry biological macromolecules such as proteins, lipids and nucleic acids, EVs influence different physiological and pathological functions of both parental and recipient cells. Although multiple pathways have been proposed for cytokine secretion beyond the classical ER/Golgi route, EVs have recently recognized as an alternative secretory mechanism. Interestingly, cytokines/chemokines exploit these vesicles to be released into the extracellular milieu, and also appear to modulate their release, trafficking and/or content. In this review, we provide an overview of the cytokines/chemokines that are known to be associated with EVs or their regulation with a focus on TNFα, IL-1β and IFNs.

  • The role of exosomes in colorectal cancer disease progression and response to therapy
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-12-18
    Laura Bracci; Francesco Lozupone; Isabella Parolini

    Colorectal cancer (CRC) is the second leading cause of cancer mortality in both of men and women worldwide. Survival of patients is significantly associated with disease stage at diagnosis. Recent studies highlighted a role of exosomes in CRC development and progression, thus raising the interest on these nanosized vesicular structures as possible biomarkers. Exosomes contain a large variety of molecules, including proteins, lipids and nucleic acids, that are exchanged between cells either within tumor microenvironment or at distant sites from the primary tumor, where they prepare a suitable soil for tumor metastases. The present review summarizes the principal effects of exosomes on CRC development, progression and resistance to therapy, and provides an update of the most recent findings on the use of exosomal molecules as diagnostic, prognostic and predictive biomarkers in CRC.

  • Anticancer Innovative therapy: Highlights from the ninth annual meeting
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-12-13
    T. Volpari; F. De Santis; A.P. Bracken; S.M. Pupa; M. Buschbeck; A. Wegner; S. Di Cosimo; MP. Lisanti; G. Dotti; M. Massaia; G. Pruneri; A. Anichini; O. Fortunato; F. De Braud; M. Del Vecchio; M. Di Nicola

    The Ninth Annual Conference of “Anticancer Innovative Therapy”, organized by Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (Fondazione IRCCS INT) and hosted by Hotel Michelangelo, was held in Milan on 25 January 2019. Cutting-edge science was presented in two main scientific sessions: i) pre-clinical evidences and new targets, and ii) clinical translation. The Keynote lecture entitled “Cancer stem cells (CSCs): metabolic strategies for their identification and eradication” presented by M. Lisanti, was one of the highlights of the conference. One key concept of the meeting was how the continuous advances in our knowledge about molecular mechanisms in various fields of research (cancer metabolism reprogramming, epigenetic regulation, transformation/invasiveness, and immunology, among others) are driving cancer research towards more effective personalized antineoplastic strategies. Specifically, recent preclinical data on the following topics were discussed: 1. Polycomb group proteins in cancer; 2. A d16HER2 splice variant is a flag of HER2 addiction across HER2-positive cancers; 3. Studying chromatin as a nexus between translational and basic research; 4. Metabolomic analysis in cancer patients; 5. CDK4-6 cyclin inhibitors: clinical activity and future perspectives as immunotherapy adjuvant; and 6. Cancer stem cells (CSCs): metabolic strategies for their identification and eradication. In terms of clinical translation, several novel approaches were presented: 1. Developing CAR-T cell therapies: an update of preclinical and clinical development at University of North Carolina; 2. Vγ9Vδ2 T-cell activation and immune suppression in multiple myeloma; 3. Predictive biomarkers for real-world immunotherapy: the cancer immunogram model in the clinical arena; and 4. Mechanisms of resistance to immune checkpoint blockade in solid tumors. Overall, the pre-clinical and clinical findings presented could pave the way to identify novel actionable therapeutic targets to significantly enhance the care of persons with cancer.

  • Insulin as an immunomodulatory hormone
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-12-03
    Gustav van Niekerk, Claudia Christowitz, Daleen Conradie, Anna-Mart Engelbrecht
  • Cancer extracellular vesicles as novel regulators of NK cell response
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-11-30
    Alessandra Soriani, Elisabetta Vulpis, Lorenzo Cuollo, Angela Santoni, Alessandra Zingoni
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-11-27
    Vanessa Pinho, Mário Fernandes, André da Costa, Raúl Machado, Andreia C Gomes

    Leukemia inhibitory factor (LIF) is a pleiotropic cytokine with several functions in health and disease ranging from inflammation to cancer. LIF is also a potential target and/or therapeutic agent for diseases such as multiple sclerosis, stroke and even psychological disorders, where the function of LIF as a neurotrophic factor has only recently been explored. In recent years, a limited number of LIF clinical trials have been completed, which partially explains the shortage of effective applications as a therapeutic agent. With the increasing interest from biotechnology companies producing recombinant LIF, this status quo will certainly change, and the potential impact of LIF in terms of disease diagnosis, treatment and management will be realized.

  • Potential role of melatonin in autoimmune diseases
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-07-16
    Chan-Na Zhao, Peng Wang, Yan-Mei Mao, Yi-Lin Dan, Qian Wu, Xiao-Mei Li, De-Guang Wang, Callan Davis, Wenbiao Hu, Hai-Feng Pan
  • 更新日期:2019-11-18
  • CD14: Biology and role in the pathogenesis of disease
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-07-03
    Zhenghao Wu, Zhenxiong Zhang, Zehua Lei, Ping Lei
  • 更新日期:2019-11-18
  • 更新日期:2019-11-18
  • Unravelling the insulin-like growth factor I-mediated photoprotection of the skin
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-11-18
    Melisa J. Andrade, Derek R. Van Lonkhuyzen, Zee Upton, Kapaettu Satyamoorthy

    Chronic exposure of human skin to solar ultraviolet radiation (UVR) induces a range of biological reactions which may directly or indirectly lead to the development of skin cancer. In order to overcome these damaging effects of UVR and to reduce photodamage, the skin’s endogenous defence system functions in concert with the various exogenous photoprotectors. Growth factors, particularly insulin-like growth factor-I (IGF-I), produced within the body as a result of cellular interaction in response to UVR demonstrates photoprotective properties in human skin. This review summarises the impact of UVR-induced photolesions on human skin, discusses various endogenous as well as exogenous approaches of photoprotection described to date and explains how IGF-I mediates UVR photoprotective responses at the cellular and mitochondrial level. Further, we describe the current interventions using growth factors and propose how the knowledge of the IGF-I photoprotection signalling cascades may direct the development of improved UVR protection and remedial strategies.

  • Senescence In Polyploid Giant Cancer Cells: A Road That Leads To Chemoresistance
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-11-15
    Deblina Bharadwaj, Mahitosh Mandal

    Cellular senescence has been associated with age-related diseases, wound healing, fibrosis, diabetes and cancer. Senescent cells lack the capacity to proliferate, but are known to aggravate tumorigenesis. The polyploid giant cells arise from the cancer cell population mainly due to genotoxic stress caused by chemotherapy and/or radiotherapy. They exhibit features of senescence and have been reported to secrete an array of cytokines, chemokines and growth factors. These small molecules can bind to their receptors located on the surface of neighboring cells and activate/deactivate relevant signaling pathways, thereby modulating the tumor microenvironment. Some of these signaling cascade(s) might play a role in imparting therapy resistance to the cancer cells. This review throws light on the incidence of senescence and how the senescent polyploid giant cells affect the tumor microenvironment. Their role in giving rise to chemoresistant cancer cell population as well as acquired chemoresistance in the neighboring cancer cells along with various potential and established therapeutic avenues has also been discussed.

  • 更新日期:2019-11-18
  • The role of interleukin-18 in pancreatitis and pancreatic cancer
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-11-09
    Zhiqiang Li, Xiao Yu, Jens Werner, Alexandr V. Bazhin, Jan G. D’Haese
  • Novel activators and small-molecule inhibitors of STAT3 in cancer
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-10-22
    Lehe Yang, Shichong Lin, Lingyuan Xu, Jiayuh Lin, Chengguang Zhao, Xiaoying Huang
  • Insight into interleukin-37: The potential therapeutic target in allergic diseases
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-10-18
    Zhaohao Huang, Lihui Xie, He Li, Xiuxing Liu, Joseph A. Bellanti, Song Guo Zheng, Wenru Su
  • Collagen and non-collagenous proteins molecular crosstalk in the pathophysiology of osteoporosis
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-09-13
    Caterina Licini, Chiara Vitale-Brovarone, Monica Mattioli-Belmonte
  • 更新日期:2019-11-18
  • Role of osteopontin in dendritic cell shaping of immune responses
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-05-10
    Annalisa Del Prete, Sara Scutera, Silvano Sozzani, Tiziana Musso
  • The role of the IL-33/ST2 axis in autoimmune disorders: Friend or foe?
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-04-03
    Xiuxing Liu, Yichen Xiao, Yuan Pan, He Li, Song Guo Zheng, Wenru Su
  • An emerging role for calcium signalling in innate and autoimmunity via the cGAS-STING axis
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-04-02
    Sabateeshan Mathavarajah, Jayme Salsman, Graham Dellaire

    Type I interferons are effector cytokines essential for the regulation of the innate immunity. A key effector of the type I interferon response that is dysregulated in autoimmunity and cancer is the cGAS-STING signalling axis. Recent work suggests that calcium and associated signalling proteins can regulate both cGAS-STING and autoimmunity. How calcium regulates STING activation is complex and involves both stimulatory and inhibitory mechanisms. One of these is calmodulin-mediated signalling that is necessary for STING activation. The alterations in calcium flux that occur during STING activation can also regulate autophagy, which in turn plays a role in innate immunity through the clearance of intracellular pathogens. Also connected to calcium signalling pathways is the cGAS inhibitor TREX1, a cytoplasmic exonuclease linked to several autoimmune diseases including systemic lupus erythematosus (SLE). In this review, we summarize these and other findings that indicate a regulatory role for calcium signalling in innate and autoimmunity through the cGAS-STING pathway.

  • Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healing
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-03-12
    Sandy W. Jere, Nicolette N. Houreld, Heidi Abrahamse

    Activated phosphatidylinositol 3 kinase/Protein kinase B (PI3K/AKT) signalling with increased or reduced mTOR and GSK3β activity influences the wound repair process. Diabetic wounds, usually ulcerated, are characterised by reduced growth factors and cellular performance. The occurrence of diabetic ulcers is linked to peripheral arterial disease, neuropathy, and wound contamination. Lasers or light emitting diodes (LEDs) provide photon energy with therapeutic benefits (Photobiomodulation-PBM), and has been broadly commended to quicken diabetic wound healing. PBM is efficient in the visible red and near-infrared electromagnetic spectrum, and fluencies ranging from 2 to 6 J/cm2. However, cellular and molecular mechanisms induced by PBM are not fully understood. In this review we discuss PBM and the PI3K/AKT pathway with specific focus on the mTOR and GSK3β downstream activity in diabetic wound healing.

  • Cytokines 2017 in Kanazawa: Looking beyond the horizon of integrated cytokine research from the sea of Japan
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2018-02-04
    David Olagnier, John Hiscott

    At the 5th Annual meeting of the International Cytokine and Interferon Society held in Kanazawa, Japan from Oct. 29–Nov. 2 2017, new research was presented in the broad field of cytokine and interferon research. The meeting provided an outstanding platform for investigators in basic science and clinical research to communicate, share and discuss their recent findings in this fast moving area of research.

  • The transition model of RTK activation: A quantitative framework for understanding RTK signaling and RTK modulator activity
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2019-11-01
    Michael D. Paul, Kalina Hristova

    Here, we discuss the transition model of receptor tyrosine kinase (RTK) activation, which is derived from biophysical investigations of RTK interactions and signaling. The model postulates that (1) RTKs can interact laterally to form dimers even in the absence of ligand, (2) different unliganded RTK dimers have different stabilities, (3) ligand binding stabilizes the RTK dimers, and (4) ligand binding causes structural changes in the RTK dimer. The model is grounded in the principles of physical chemistry and provides a framework to understand RTK activity and to make predictions in quantitative terms. It can guide basic research aimed at uncovering the mechanism of RTK activation and, in the long run, can empower the search for modulators of RTK function.

  • Targeting T-helper 9 cells and interleukin-9 in autoimmune diseases.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2014-09-13
    Hai-Feng Pan,Rui-Xue Leng,Xiang-Pei Li,Song Guo Zheng,Dong-Qing Ye

    CD4(+) T helper (Th) cells are central to the modulation of immune responses, with distinct effector subsets defined by their lineage-specific transcription factor expression, cytokines production and immune function. Th9, one of the recently defined subsets of Th cells, are identified by the potent production of interleukin-9 (IL-9). Recent studies have indicated that Th9 cells and IL-9 are closely associated with several autoimmune diseases, such as systemic lupus erythematosus (SLE),experimental autoimmune encephalitis (EAE) and systemic sclerosis (SSc). In the present review, we will briefly discuss the biological features of Th9/IL-9 and summarize recent advances focusing on the role of Th9/IL-9 in the pathogenesis and possible treatment in autoimmune diseases using anti-Th9 target.

  • The multifaceted relationship between IL-10 and adaptive immunity: putting together the pieces of a puzzle.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2004-01-30
    Simone Mocellin,Francesco Marincola,Carlo Riccardo Rossi,Donato Nitti,Mario Lise

    Interleukin-10 (IL-10) is a pleiotropic cytokine that modulates the function of several adaptive immunity-related cells. Although generally considered an immunosuppressive molecule, IL-10 possesses immunostimulatory properties in several in vitro and in vivo models. These very different outcomes are believed to depend upon experimental conditions, the dominant immune effector mediating a given immune response, the timing of IL-10 production/administration, and IL-10 dose and/or location of expression. In the present work, we review the current knowledge regarding IL-10 activity on adaptive immunity related cells, emphasize new insights on IL-10 molecular/cellular targets, and summarize the available data on the relationship between IL-10 and some pathological conditions (e.g. infectious diseases, autoimmunity, allergy, cancer and transplantation) involving adaptive immunity.

  • IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2004-01-30
    Steeve Kwan Tat,Marc Padrines,Sandrine Théoleyre,Dominique Heymann,Yannick Fortun

    All osteogenic cells (osteoclasts, osteoblasts) contribute individually to bone remodeling. Their cellular interactions control their cellular activities and the bone remodeling intensity. These interactions can be established either through a cell-cell contact, involving molecules of the integrin family, or by the release of many polypeptidic factors and/or their soluble receptor chains. These factors can act directly on osteogenic cells and their precursors to control differentiation, formation and functions (matrix formation, mineralization, resorption...). Here, we present the involvement of three groups of cytokines which seem to be of particular importance in bone physiology: interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) (TNF-alpha)/IL-1, and the more recently known triad osteoprotegerin (OPG)/receptor activator of NF-kappaB (RANK)/RANK ligand (RANKL). The interactions between these three groups are presented within the framework of bone resorption pathophysiology such as tumor associated osteolysis. The central role of the OPG/RANK/RANKL triad is pointed out.

  • The Class II cytokine receptor (CRF2) family: overview and patterns of receptor-ligand interactions.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2004-01-30
    Jerome A Langer,E Cali Cutrone,Sergei Kotenko

    Expanded genomic information has driven the discovery of new members of the human Class II family of cytokine receptors (CRF2), which now includes 12 proteins. The corresponding cytokines have been identified, paired with their receptors and initially characterized for function. These cytokines include: a new human Type I IFN, IFN-kappa; molecules related to IL-10 (IL-19, IL-20, IL-22, IL-24, IL-26); and IFN-lambdas (IL-28/29), which have antiviral and cell stimulatory activities reminiscent of Type I IFNs, but act through a distinct receptor. In response to ligand binding, the CRF2 proteins form heterodimers, leading to cytokine-specific cellular responses; these diverse physiological functions are just beginning to be explored. Progress in structural and mutational analysis of ligand-receptor interactions now presents a more reliable framework for understanding receptor-ligand interactions, and for predicting key regions in less well studied members of the CRF2 family. The relationships between the CRF2 proteins will be summarized, as will the progress in identifying patterns of receptor interactions with ligands.

  • Inducible nitric oxide synthase activation by interleukin-17.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2004-01-30
    Djordje Miljkovic,Vladimir Trajkovic

    Interleukin-17 (IL-17) is a proinflammatory T cell cytokine presumably involved in physiological responses to infection, but also in immunopathology of autoimmune disorders such as rheumatoid arthritis. The proinflammatory action of IL-17 depends considerably on its ability to trigger the expression of inducible nitric oxide (NO) synthase (iNOS), an enzyme responsible for the generation of cytotoxic and immunoregulatory free radical NO. Here we discuss the role of IL-17 in the cytokine network controlling iNOS expression, and analyze signaling pathways employed by IL-17 for the initiation of iNOS gene transcription. We also propose biological consequences of IL-17-mediated NO release that could be relevant for the mechanisms or therapy of autoimmune and inflammatory disorders.

  • Dual intracellular signaling by proteolytic cleavage of membrane-anchored heparin-binding EGF-like growth factor.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2004-01-30
    Daisuke Nanba,Shigeki Higashiyama

    Heparin-binding EGF-like growth factor (HB-EGF), a member of the EGF family, is synthesized as a membrane-anchored precursor (proHB-EGF) that is cleaved to release a soluble HB-EGF by specific metalloproteases. Proteolytic cleavage of proHB-EGF yields amino- and carboxy-terminal fragments (HB-EGF and HB-EGF-C). Recent studies indicate that the processing of proHB-EGF is strictly regulated and involved in a variety of biological processes and that not only HB-EGF but also HB-EGF-C functions as a signaling molecule. ProHB-EGF generates dual intracellular signaling molecules by its proteolytic cleavage.

  • The transforming growth factor-beta superfamily of receptors.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2004-01-30
    Mark de Caestecker

    The transforming growth factor-beta (TGF-beta) superfamily of receptors comprises two groups of transmembrane serine-threonine kinase receptors, so called type I, and type II receptors, that are activated following engagement by members of the TGF-beta superfamily of ligands. These events specify diverse downstream responses that are differentially regulated by controlling access and activation of the ligands, their receptors and downstream substrates in different cell types. The purpose of this review is to describe the biochemical properties of these receptors, focusing specifically on the mechanisms regulating receptor/ligand interactions and activation in mammalian cells.

  • Neurotrophins in inflammatory lung diseases: modulators of cell differentiation and neuroimmune interactions.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-10-18
    Wolfgang Andreas Nockher,Harald Renz

    Chronic inflammatory lung diseases represent a group of severe diseases with increasing prevalence as well as epidemiological importance. Inflammatory lung diseases could result from allergic or infectious genesis. There is growing evidence that the immune and nervous system are closely related not only in physiological but also in pathological reactions in the lung. Extensive communications between neurons and immune cells are responsible for the magnitude of airway inflammation and the development of airway hyperreactivity, a consequence of neuronal dysregulation. Neurotrophins are molecules regulating and controlling this crosstalk between the immune and peripheral nervous system (PNS) during inflammatory lung diseases. They are constitutively expressed by resident lung cells and produced in increasing quantities by immune cells invading the airways under inflammatory conditions. They act as activation, differentiation and survival factors for cells of both the immune and nervous system. This article will review the most recent data of neurotrophin signaling in the normal and inflamed lung and as yet unexplored, roles of neurotrophins in the complex communication within the neuroimmune network.

  • Cytokine regulation of pulmonary fibrosis in scleroderma.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-10-18
    Sergei P Atamas,Barbara White

    Pulmonary fibrosis occurs in up to 70% of scleroderma patients and progresses to cause severe restrictive lung disease in about 15% of patients. The mechanisms that cause pulmonary fibrosis in scleroderma remain incompletely understood. Increased amounts of mRNA or protein for multiple profibrotic cytokines and chemokines have been identified in lung tissue or broncholveolar lavage samples from scleroderma patients, when compared to healthy controls. These cytokines include transforming growth factor (TGF)-beta, connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), oncostatin M (OSM), monocyte chemotactic factor-1 and pulmonary and activation-regulated chemokine (PARC). Potential cellular sources of these profibrotic cytokines and chemokines in scleroderma lung disease include alternatively activated macrophages, activated CD8+ T cells, eosinophils, mast cells, epithelial cells and fibroblasts themselves. This review summarizes the literature on involvement of cytokines and chemokines in the development of pulmonary fibrosis in scleroderma.

  • Neurotrophins and lung disease.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-10-18
    Gary W Hoyle

    Neurotrophins are growth factors that exert multiple actions on neuronal and nonneuronal cells. Neurotrophin receptors are expressed on central and peripheral neurons, lymphocytes, monocytes, mast cells, and fibroblasts. In accordance with the distribution of their receptors, neurotrophins control the development and function of neurons and regulate inflammatory processes. Production of neurotrophins is altered in asthma, lung cancer, and pulmonary fibrosis. Evidence from animal models has implicated nerve growth factor (NGF) as a mediator of pulmonary inflammation, bronchoconstriction, and airway hyperreactivity, all of which are hallmarks of asthma. NGF regulates the growth of lung tumor cells and cultured lung fibroblasts. Thus neurotrophins, particularly NGF, are candidate molecules for regulating disease processes in asthma, lung cancer, and pulmonary fibrosis.

  • Cytokine-mediated inflammation in acute lung injury.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-10-18
    Richard B Goodman,Jérôme Pugin,Janet S Lee,Michael A Matthay

    Clinical acute lung injury (ALI) is a major cause of acute respiratory failure in critically ill patients. There is considerable experimental and clinical evidence that pro- and anti-inflammatory cytokines play a major role in the pathogenesis of inflammatory-induced lung injury from sepsis, pneumonia, aspiration, and shock. A recent multi-center clinical trial found that a lung-protective ventilatory strategy reduces mortality by 22% in patients with ALI. Interestingly, this protective ventilatory strategy was associated with a marked reduction in the number of neutrophils and the concentration of pro-inflammatory cytokines released into the airspaces of the injured lung. Further research is needed to establish the contribution of cytokines to both the pathogenesis and resolution of ALI.

  • Cytokine-directed therapies for the treatment of chronic airway diseases.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-10-18
    Peter J Barnes

    Multiple cytokines play a critical role in orchestrating and perpetuating inflammation in asthma and chronic obstructive pulmonary disease (COPD) and several specific cytokine and chemokine inhibitors now in development as future therapy for these diseases. Anti-IL-5 antibody markedly reduces peripheral blood and airway eosinophils, but does not appear to be effective in symptomatic asthma. Inhibition of IL-4 despite promising early results in asthma has been discontinued and blocking IL-13 might be more effective. Inhibitory cytokines, such as IL-10, interferons and IL-12 are less promising, as systemic delivery produces side effects. Inhibition of TNF-alpha may be useful in severe asthma and for treating severe COPD with systemic features. Many chemokines are involved in the inflammatory response of asthma and COPD and several small molecule inhibitors of chemokine receptors (CCR) are in development. CCR3 antagonists (which block eosinophil chemotaxis) and CXCR2 antagonists (which block neutrophil and monocyte chemotaxis) are in clinical development for asthma and COPD, respectively. Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful; several such classes of drug are now in clinical development and any risk of side effects with these non-specific inhibitors may be reduced by the inhaled route.

  • Chemokines and cytokines: axis and allies in asthma and allergy.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-10-18
    Jane M Schuh,Kate Blease,Steven L Kunkel,Cory M Hogaboam

    Allergic asthma can be precipitated by many factors. For the atopic person, fungus, pollen, dust mites, cockroach antigens, and diesel exhaust are all agents that may trigger an allergic attack. Cytokines and chemokines are integral mediators of fungal asthma. From the earliest time points, they recruit and activate the cells required for the clearance of fungus as well as being critical factors involved in the immunopathology of this disease. In the final analysis, it is clear that these mediators can act to the benefit or the detriment of the host.

  • Immunomodulatory cytokines in asthmatic inflammation.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-10-18
    Elizabeth L Lynch,Frédéric F Little,Kevin C Wilson,David M Center,William W Cruikshank

    The development of asthmatic inflammation involves a complex array of cytokines that promote the recruitment and activation of a number of different immune cells. While factors involved in initiating and establishing inflammation are well characterized, the process by which this pro-inflammatory cascade is regulated is less well understood. The identification and characterization of immunomodulatory cytokines in asthma has been a difficult proposition. Many of the putative regulatory factors have pleiotropic bioactivities and have been characterized as pro-inflammatory in association with certain pathologic conditions. This chapter addresses the potential role of several endogenous factors which appear to attenuate asthmatic inflammation. Understanding the integration of these factors into the regulation of the inflammatory process will likely result in novel therapeutic approaches.

  • The role of osteopontin in lung disease.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-10-18
    Anthony O'Regan

    Osteopontin (Opn) is a multifunctional protein independently discovered by investigators from diverse scientific backgrounds and implicated in a broad array of pathological processes. Opn exists both intra- and extracellularly and in numerous pre- and post-translational isoforms. Structurally Opn resembles a matrix protein yet it has well-characterized cytokine like properties including the regulation of cellular migration and cell-mediated immunity. It has thus been classified as both a matricellular protein and a cytokine. Opn is among the most abundantly expressed proteins in a range of lung diseases and has been shown to regulate aspects of pulmonary granuloma formation, fibrosis, and malignancy. Future studies will explore the diagnostic and therapeutic potential of modulating the function of Opn in vivo.

  • Chemokines and tuberculosis.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-10-18
    Holly M Scott Algood,John Chan,JoAnne L Flynn

    Mycobacterium tuberculosis is a respiratory pathogen responsible for tuberculosis. A primary pathologic feature of M. tuberculosis infection is the formation of a granuloma. Immune cells migrate to the lung and then through the lung to the site of infection to form a granuloma. This structure contains the infection, and is often maintained for a long period of time. The signals responsible for granuloma formation and maintenance are largely unknown. Since chemokines and chemokine receptors direct cells to specific sites within the tissues, it is plausible that these cells participate in granuloma formation. In this review, the current literature on chemokines and M. tuberculosis infection, as well as the specific role that tumor necrosis factor alpha (TNF-alpha) plays in granuloma formation and chemokine expression are discussed.

  • Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-09-02
    Hong Ruan,Harvey F Lodish

    Insulin resistance is a fundamental defect that precedes the development of the full insulin resistance syndrome as well as beta cell failure and type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha), a paracrine/autocrine factor highly expressed in adipose tissues of obese animals and human subjects, is implicated in the induction of insulin resistance seen in obesity and type 2 diabetes. Here, we review several molecular aspects of adipose tissue physiology, and highlight the direct effects of TNF-alpha on the functions of adipose tissue including induction of lipolysis, inhibition of insulin signaling, and alterations in expression of adipocyte important genes through activation of NF-kappaB, as well as their pertinence to insulin sensitivity of adipocytes. We also review the ability of TNF-alpha to inhibit synthesis of several adipocyte-specific proteins including Acrp30 (adiponectin) and enhance release of free fatty acids (FFAs) from adipose tissue, and discuss how these factors may act as systemic mediators of TNF-alpha and affect whole body energy homeostasis and overall insulin sensitivity. On the basis of these mechanisms, we examine the therapeutic potential of blocking specific autocrine/paracrine signaling pathways in adipocytes, particularly those involving NF-kappaB, in the treatment of type 2 diabetes.

  • Transforming growth factor beta in cardiovascular development and function.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-09-02
    Mohamad Azhar,Jo El J Schultz,Ingrid Grupp,Gerald W Dorn,Pierre Meneton,Daniel G M Molin,Adriana C Gittenberger-de Groot,Thomas Doetschman

    Transforming growth factor betas (TGFbetas) are pleiotropic cytokines involved in many biological processes. Genetic engineering and tissue explanation studies have revealed specific non-overlapping roles for TGFbeta ligands and their signaling molecules in development and in normal function of the cardiovascular system in the adult. In the embryo, TGFbetas appear to be involved in epithelial-mesenchymal transformations (EMT) during endocardial cushion formation, and in epicardial epithelial-mesenchymal transformations essential for coronary vasculature, ventricular myocardial development and compaction. In the adult, TGFbetas are involved in cardiac hypertrophy, vascular remodeling and regulation of the renal renin-angiotensin system. The evidence for TGFbeta activities during cardiovascular development and physiologic function will be given and areas which need further investigation will be discussed.

  • Transcription of the platelet-derived growth factor A-chain gene.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-09-02
    David M Kaetzel

    The molecular mechanisms which control the transcription of growth factor genes underlie such diverse biological processes as embryonic development, cellular differentiation and wound healing. Moreover, disruption of these controls is implicated in the development and progression of a wide variety of human diseases, including cancer, atherosclerosis and fibrotic disease. This review highlights progress made in the study of the gene encoding platelet-derived growth factor A-chain (PDGF-A) from the perspective of its normal patterns of expression, as well as possible mechanisms leading to dysregulation and disease. A particular focus has been placed on the identification and characterization of specific DNA elements, DNA-binding proteins and other aspects of transcriptional regulation involved in activation and repression of the human PDGF-A promoter.

  • The CC chemokine CCL20 and its receptor CCR6.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-09-02
    Evemie Schutyser,Sofie Struyf,Jo Van Damme

    CCL20, alternatively named liver and activation-regulated chemokine (LARC), macrophage inflammatory protein-3alpha (MIP-3alpha) or Exodus-1, is the only chemokine known to interact with CC chemokine receptor 6 (CCR6), a property shared with the antimicrobial beta-defensins. The ligand-receptor pair CCL20-CCR6 is responsible for the chemoattraction of immature dendritic cells (DC), effector/memory T-cells and B-cells and plays a role at skin and mucosal surfaces under homeostatic and inflammatory conditions, as well as in pathology, including cancer and rheumatoid arthritis. In this review, the discovery, the gene and protein structure, the in vitro biological activities, the cell and inducer specific expression and the tissue distribution of CCL20 and CCR6 are discussed.

  • Cytokine knockouts in contact hypersensitivity research.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-09-02
    Binghe Wang,Clemens Esche,Adam Mamelak,Irwin Freed,Hideaki Watanabe,Daniel N Sauder

    Contact hypersensitivity (CHS) is a Langerhans cell (LC)-dependent, T cell-mediated cutaneous immune response. CHS reflects a culmination of LC activities in vivo: uptake of epicutaneous antigens, migration into lymph nodes, and presentation of antigens to naïve T cells. Although studies have suggested involvement of the cytokine network in LC migration and CHS initiation, the in vivo function of individual cytokines remains largely unknown. Gene targeting technology has made it possible to study in vivo functions of cytokines through gene-targeted knockout (KO) mice deficient in a given cytokine or its receptor. A variety of cytokine knockouts have been used to assign biological functions to specific cytokines in CHS. These studies have contributed significantly to our understanding of molecular mechanisms underlying CHS.

  • Lineage-specific negative regulation of STAT-mediated signaling by proteolytic processing.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-09-02
    Hiroshi Nakajima,Kotaro Suzuki,Itsuo Iwamoto

    Accumulating evidence suggests that STAT-mediated signaling plays critical roles in cell differentiation and/or cell expansion and that in turn, STAT-mediated signaling is regulated strictly by many mechanisms. In murine mast cells, when Stat6 is activated by IL-4 and translocated to the nucleus, Stat6 is cleaved by a nucleus-associated protease (namely Stat6-protease). Similarly, the activated Stat5 is cleaved by a protease (Stat5-protease) in the nucleus of myeloid progenitors. These STAT proteases cleave the corresponding STAT proteins at the carboxyl-terminus and the resultant STAT proteins function as dominant negative molecules. Functionally, Stat6-protease protects mast cells from Stat6-dependent growth inhibition while Stat5-protease maintains the immature state of myeloid progenitors. In addition, it has been shown that the activated Stat3 is cleaved in mature neutrophils. These findings indicate that the proteolytic processing of STAT proteins by the nucleus-associated protease functions as a lineage-specific negative-regulator of STAT-mediated signaling.

  • New insights on the involvement of Nerve Growth Factor in allergic inflammation and fibrosis.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-09-02
    Alessandra Micera,Ilaria Puxeddu,Luigi Aloe,Francesca Levi-Schaffer

    Nerve Growth Factor (NGF), that was originally discovered for its properties of stimulating growth and differentiation of neurons, is now also considered responsible for several activities in the immune system and beyond. Mast cells and eosinophils, key cells of allergic inflammation, are a source of NGF and are influenced by it. These observations have prompted studies on NGF in allergy and tissue repair. Recent evidences link NGF and these two processes. While NGF is clearly a new tool in the management of untreatable ulcers, its role in allergic inflammation, although appearing to be pro-inflammatory, is still not clearly defined.

  • The biology of IL-12: coordinating innate and adaptive immune responses.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-09-02
    Wendy T Watford,Masato Moriguchi,Akio Morinobu,John J O'Shea

    Cytokines play critical roles in regulating all aspects of immune responses, including lymphoid development, homeostasis, differentiation, tolerance and memory. Interleukin (IL)-12 is especially important because its expression during infection regulates innate responses and determines the type and duration of adaptive immune response. IL-12 induces interferon-gamma (IFN-gamma) production by NK, T cells, dendritic cells (DC), and macrophages. IL-12 also promotes the differentiation of naïve CD4+ T cells into T helper 1 (Th1) cells that produce IFN-gamma and aid in cell-mediated immunity. As IL-12 is induced by microbial products and regulates the development of adaptive immune cells, IL-12 plays a central role in coordinating innate and adaptive immunity. IL-12 and the recently identified cytokines, IL-23 and IL-27, define a family of related cytokines that induce IFN-gamma production and promote T cell expansion and proliferation.

  • Viruses and the TNF-related cytokines, an evolving battle.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-06-06
    Chris A Benedict

    Tumor necrosis factor (TNF)-related cytokines are critical effector molecules in the immune response to viral pathogens. Engagement of the TNF receptors by their cognate ligands activates apoptotic and non-apoptotic signaling pathways, both of which can mediate antiviral activity. In response, viruses have evolved mechanisms to inhibit signaling by some cytokines of the TNF superfamily. These strategies are largely unique to each class of virus, but are similar in that they all target key regulatory checkpoints of the TNF pathway. In recent years, studies directed towards dissecting the mechanisms of TNF signaling and the viral retort have led to several significant discoveries, and form the basis for this review.

  • Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-06-06
    Alexandru Almasan,Avi Ashkenazi

    Apo2 ligand or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) is one of several members of the TNF gene superfamily that induce apoptosis through engagement of death receptors. Apo2L/TRAIL is unusual as compared to any other cytokine as it interacts with a complex system of receptors: two pro-apoptotic death receptors and three anti-apoptotic decoys. This protein has generated tremendous excitement as a potential tumor-specific cancer therapeutic because, as a stable soluble trimer, it selectively induces apoptosis in many transformed cells but not in normal cells. Transcriptional activation of Apo2L/TRAIL by interferons (IFNs) through specific regulatory elements in its promoter, and possibly by a number of other cytokines, reveals its possible involvement in the activation of natural killer cells, cytotoxic T lymphocytes, and dendritic cells. In this review, we focus on the apoptosis signaling pathways stimulated by Apo2L/TRAIL, summarize what is known to date about the physiological role of this ligand and the potential for its application to cancer therapy.

  • Biology of FasL.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-06-06
    Hae-ock Lee,Thomas A Ferguson

    FasL (CD95L) is a well-known and well-characterized death-inducing ligand. Spontaneous mutations in FasL and its cognate receptor Fas (CD95) have helped understand the role of these molecules in the disease. Once thought to be mainly involved in the homeostasis of immune system, the territory of FasL regulation has been expanded to angiogenesis and tumor progression. Here, we review what is currently known about the role of FasL in many areas of biology.

  • The TNF family members BAFF and APRIL: the growing complexity.
    Cytokine Growth Factor Rev. (IF 5.458) Pub Date : 2003-06-06
    Fabienne Mackay,Christine Ambrose

    B cell activating factor belonging to the TNF family (BAFF) and apoptosis-inducing ligand (APRIL) are two related members of the TNF ligand superfamily. Although they share two receptors, TACI and BCMA, transgenic and knockout mice in this system reveal that their functions are not redundant. BAFF is a critical survival/maturation factor for peripheral B cells and this activity is mediated through a BAFF-specific receptor, BAFF-R. Overexpression of BAFF has been linked to autoimmune disease and aspects of B cell neoplasia. APRIL appears to play a role in T-independent type II antigen responses and T cell survival, but can also induce proliferation/survival of non-lymphoid cells. Elevated expression of APRIL has been found in some tumor cell lines and in tumor tissue libraries. Therapies designed to inhibit the BAFF and APRIL pathways holds great promise for the future.

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上海纽约大学William Glover