Open Access, Peer-reviewed
pISSN 1598-2629 eISSN 2092-6685
Indexed in PubMed, Scopus and SCIE
    Immune Netw. 2020 Dec;20(6):e47. English.
    Published online Dec 21, 2020.
    https://doi.org/10.4110/in.2020.20.e47
    Copyright © 2020. The Korean Association of Immunologists
    Review

    Immunotherapy of Autoimmune Diseases with Nonantibiotic Properties of Tetracyclines

    Chan-Su Park,1 Sang-Hyun Kim,2 and Chong-Kil Lee2
      • 1Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
      • 2Department of Pharmaceutics, College of Pharmacy, Chungbuk National University, Cheongju 28644, Korea.
    • Correspondence to Chong-Kil Lee. Department of Pharmaceutics, College of Pharmacy, Chungbuk National University, Chungdae-ro 1, Seowon-gu, Cheongju 28644, Korea. Email: cklee@chungbuk.ac.kr
    Received September 26, 2020; Accepted December 08, 2020.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Tetracyclines, which have long been used as broad-spectrum antibiotics, also exhibit a variety of nonantibiotic activities including anti-inflammatory and immunomodulatory properties. Tetracyclines bind to the 30S ribosome of the bacteria and inhibit protein synthesis. Unlike antimicrobial activity, the primary molecular target for the nonantibiotic activity of tetracycline remains to be clarified. Nonetheless, the therapeutic efficacies of tetracyclines, particularly minocycline and doxycycline, have been demonstrated in various animal models of autoimmune disorders, such as multiple sclerosis, rheumatoid arthritis, and asthma. In this study, we summarized the anti-inflammatory and immunomodulatory activities of tetracyclines, focusing on the mechanisms underlying these activities. In addition, we highlighted the on-going or completed clinical trials with reported outcomes.

    Keywords
    Minocycline; Doxycycline; Anti-inflammatory activity; Immunomodulatory activity; Autoimmune disease; Clinical trial

    INTRODUCTION

    Tetracyclines are a group of broad spectrum antibiotics active against a wide range of pathogenic bacteria, including Chlamydia, Rickettia, and Mycoplasma (1). Tetracyclines bind to and inhibit the functions of both prokaryotic 70S and eukaryotic 80S ribosomes. However, they inhibit the growth of bacterial cells, but not that of animal cells, because in bacteria they penetrate using an efficient and specific transport system, whereas in animal cells their internal concentration never attains the inhibitory levels (1). Chlortetracycline and oxytetracycline, purified from the fermentation broth of Streptomyces sp., are classified as natural tetracyclines and are the first members of the tetracycline family introduced as clinical antibacterial chemotherapeutics. Later, numerous semisynthetic derivatives, including minocycline and doxycycline, have been developed and introduced for clinical use (2).

    In addition to their well-known antibiotic activities, tetracyclines, especially minocycline and doxycycline, exhibit great therapeutic potential in various animal models of neurological diseases, including stroke, spinal-cord injury, Parkinson's disease, and Huntington's disease (3, 4, 5). Tetracyclines are also beneficial in the treatment of various autoimmune disorders, such as multiple sclerosis (MS), rheumatoid arthritis (RA), and asthma (6, 7, 8). Recently, doxycycline has even been proposed as a potential anti-cancer drug based on its inhibitory effects on cancer cell proliferation and metastasis (9).

    Although the mechanism of action for the antibiotic activities of tetracyclines is well known, the exact mechanism of action underlying their nonantibiotic activities is yet to be fully understood. For instance, multiple mechanisms have been proposed for the nonantibiotic activity of minocycline. These include the inhibition of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 (10, 11, 12), inhibition of proinflammatory enzymes such as inducible nitric oxide synthetase (iNOS) and matrix metalloproteinases (MMPs) (13, 14), downregulation of MHC class II expression in microglia and macrophages (15), suppression of T cell proliferation and activation (16, 17), and induction of tolerogenic dendritic cells (DCs) (18, 19).

    In this review, we summarized the anti-inflammatory and immunomodulatory activities of tetracyclines, especially minocycline and doxycycline, and the clinical trials that are being carried out to treat autoimmune disorders with these antibiotics.

    ANTI-INFLAMMATORY AND IMMUNOMODULATORY ACTIVITIES

    Inhibition of T cell proliferation and cytokine production

    The suppressive effects of tetracyclines on T cells have been described earlier. Tetracyclines, in particular doxycycline, have potent suppressive effects on delayed-type hypersensitivity (DTH) response to sheep red blood cells (SRBCs) in mice, although they have no significant suppressive effects on the Ab production to SRBC (20). Minocycline suppresses the mitotic response of lymphocytes in whole blood cultures with phytohemagglutinin (21). Minocycline inhibits TCR/CD3-induced IL-2, IFN-γ, and TNF-α production by CD4+ synovial T cell clones derived from the synovium (22). The production of TNF-α and IFN-γ by stimulated PBMCs are also inhibited by minocycline (16). Further, minocycline suppresses NFAT1-mediated transcriptional activation in human CD4+ T cells (23).

    Suppression of Ag presentation capacity

    Tetracyclines, in particular minocycline, inhibit the processing and presentation of tetanus toxoid by human peripheral blood Ag presenting cells (APCs) to the human T cells. This inhibition was not observed when tetanus toxoid was first incubated with APCs before the addition of minocycline, indicating that minocycline inhibits the intracellular processing of tetanus Ag (24). Recently, we showed that DCs generated from the bone marrow cells in the presence of minocycline together with GM-CSF and IL-4 (Mino-DCs) demonstrated the characteristics of regulatory DCs. Mino-DCs were impaired in MHC class II-restricted exogenous Ag presentation, inflammatory cytokine production, and alloantigen-specific T cell priming. However, they increased in the production of IL-10 and expansion of CD4+CD25+Foxp3+ T regulatory cells (18, 19).

    Inhibition of microglial cell function

    Numerous studies have reported tetracyclines to inhibit the activation and proliferation of microglial cells, macrophage-like cells located throughout the brain and spinal cord. Inflammation induced and aggravated by microglial cells is one of the reasons responsible for the ischemic neuronal death. Thus, compounds inhibiting the activation and proliferation of microglial cells may have a therapeutic value as anti-ischemic drugs. Previous studies reported the therapeutic efficacy of tetracyclines in a rat model of transient middle cerebral artery occlusion and in a gerbil model of forebrain ischemia (25, 26). Since then, the protective effects of tetracycline have been explored in various models of central nervous system diseases, including MS (17, 27), Parkinson's disease (28, 29), nerve injury-induced neuropathic pain (30), and neuroinflammation (31). Minocycline appears to exert neuroprotective activity via the inhibition of microglial activation and proliferation (26, 29, 32).

    Inhibition of the production of proinflammatory cytokines

    One of the major nonantibiotic activities of tetracyclines is the inhibition of inflammatory cytokine production by the immune cells. Numerous studies have shown that tetracyclines, especially minocycline and doxycycline, suppress the production of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 (18, 33, 34, 35, 36). The inhibitory effect of doxycycline on proinflammatory cytokine production has also been demonstrated in various disease models, including neonatal rat hypoxia-ischemia (36), murine experimental autoimmune encephalitis (EAE) (18), and murine polymicrobial sepsis (37). The in vivo efficacy of doxycycline has also been demonstrated in patients with dengue hemorrhagic fever (38). Since proinflammatory cytokines play an essential role in the process of inflammation, blocking their production using tetracyclines provide the theoretical basis for the clinical application of tetracyclines in the treatment of inflammation-based diseases.

    Inhibition of MMPs

    The best-characterized nonantibiotic activity of tetracyclines is their ability to inhibit MMPs. In 1983, minocycline has been reported to inhibit tissue collagenolytic enzyme activity in gingiva of diabetic rats by a mechanism unrelated to its antibacterial efficacy (39). Later, it was confirmed that some of the tetracyclines, including doxycycline, inhibit MMPs. MMPs are a family of zinc-dependent protease, and involves in the metabolism of connective tissue and in the process of cell formation (40, 41). MMPs can be subdivided based on the substrate specificity into collagenases, gelatinases, stromelysins, matrilysins, membrane-bound MMPs, and other MMPs (42). MMPs are secreted by many cells including fibroblasts, vascular smooth muscle, and leukocytes, and are involved in various physiological processes such as inflammation, immunity, neurite growth and bone remodeling (43). Increased MMP activity is associated with the pathophysiology of various immune disorders, including RA, inflammatory bowel diseases, and some neurodegenerative diseases (27, 44). MMPs that are secreted from activated T cells or tissues play an important role in the pathogenesis of EAE and MS (45). While tetracyclines affect a number of MMPs, minocycline and doxycycline are especially effective in inhibiting MMP-2 and MMP-9 (6).

    Inhibition of iNOS

    Inhibition of iNOS activity is also a common feature of most tetracyclines. Overproduction of nitric oxide (NO) has been implicated in a variety of inflammatory and autoimmune diseases including RA, systemic lupus erythematosus, ulcerative colitis, and Crohn's disease (46). NO is the major mediator of tissue injury in arthritis (47). Doxycycline and minocycline inhibit iNOS in LPS-stimulated murine macrophages (48, 49) and also in cultures of cartilage cuts obtained from patients with advanced osteoarthritis (OA) undergoing knee replacement surgery, which spontaneously release NO sufficient to cause cartilage damage (48). In cultures of cartilage cuts, doxycycline or minocycline inhibits iNOS activity through the inhibition of NOS mRNA expression. In a murine model of dextran sodium sulfate-induced acute colitis, treatment with minocycline significantly diminished the mortality rate and attenuated the severity of the disease (50). Mechanistic investigation showed that minocycline administration suppresses the iNOS expression along with the inhibition of proinflammatory cytokine secretion.

    Inhibition of inflammation-associated molecules

    Minocycline and doxycycline inhibit secretory phospholipase A2 (PLA2), an enzyme with an important role in inflammatory processes. Structural analysis showed that minocycline binds to the hydrophobic cleft located at the entrance of the active site in the calcium (Ca2+) binding loop of PLA2 (51, 52). Thus, the binding of the substrate molecules to the active site is inhibited, resulting in the inhibition of enzymatic activity (52).

    Cyclooxygenase-2 (COX-2), increased during inflammation, leads to the synthesis of prostaglandins. Minocycline inhibited COX-2 expression and subsequently production of prostaglandin E2 (PGE2) in a rat model of transient middle cerebral artery occlusion (26). A recent study showed that minocycline significantly reduces the expression of COX-2 and PGE2 in rats with systemic LPS-induced spinal cord inflammation (53). However, there is a report showing tetracyclines to enhance the PGE2 production in RAW 264.7 cells (54).

    The mechanisms for the nonantibiotic activity of tetracyclines, especially minocycline and doxycycline, are summarized in Fig. 1. Unlike the antimicrobial activity, multiple mechanisms have been proposed for the nonantibiotic activity of tetracyclines.

    Figure 1
    Mechanisms for the nonantibiotic activities of minocycline and doxycycline.

    CLINICAL TRIALS BASED ON ANTI-INFLAMMATORY AND IMMUNOMODULATORY ACTIVITY OF TETRACYCLINES

    Based on the successful therapeutic outcomes of minocycline or doxycycline in animal models, various clinical trials have been completed or ongoing in patients with autoimmune diseases such as MS, RA, asthma, Alzheimer's disease (AD), and type 2 diabetes. Clinical trials ongoing or with reported outcomes that have been registered on ClinicalTrials.gov portal are summarized in Table 1.

    Table 1
    Clinical trials ongoing or with reported outcomes that have been registered on ClinicalTrials.gov

    MS

    Three clinical trials have been completed with positive results and one clinical trial is ongoing. The first clinical trial for MS treatment examined the add-on effect of oral minocycline on subjects treated daily with Copaxone®, an injectable glatiramer acetate, in relapsing-remitting MS (RRMS). The combination treatment with minocycline and glatiramer acetate reduced the risk of relapse and was found to be safe and well tolerated (55). Another clinical trial determined whether oral minocycline reduced the conversion from a first demyelinating event, also known as clinically isolated syndrome, to MS. Results revealed that 100 mg of minocycline, administered orally twice daily, to significantly lower the conversion of clinically isolated syndrome to MS, as defined according to the 2005 McDonald criteria (56). Doxycycline was also examined to treat MS. The related study evaluated the efficacy, safety, and tolerability of combination therapy with intramuscular IFN-β1a and oral doxycycline in patients with RRMS having breakthrough disease activity. The clinical trial results showed combination of intramuscular IFN-β1a and oral doxycycline treatment to be effective, safe, and well tolerated (57). Currently, another trial is ongoing to confirm the benefits of minocycline in MS patients who have had a first demyelinating event in the past 180 days and at least possesses 2 brain T2 lesions of minimum 3 mm in diameter (NCT04291456). A similar clinical trial was performed with doxycycline by Iranian scientists. They examined the efficacy of doxycycline as an add-on to IFN-β1a in the treatment of MS and claimed that combination therapy can decrease the relapse rate and improve the expanded disability status scale scores (58). Collectively, the clinical trial results highlighted minocycline as an effective and safe antibiotic for treating MS.

    RA

    Although not listed in the ClinicalTrials.gov portal, several clinical studies performed worldwide have shown tetracyclines, especially minocycline and doxycycline, to significantly reduce the severity of RA (59, 60, 61). In ClinicalTrials.gov portal, 2 clinical trials are listed as complete. One clinical trial aimed to determine whether a combination of methotrexate and minocycline works better than methotrexate alone in early RA (NCT00579644). The results of this study are awaited. The efficacy of doxycycline in the treatment of RA was also tested in combination with methotrexate. This study showed that initial therapy with methotrexate and doxycycline is superior to treatment with methotrexate alone in patients with early seropositive RA (62). Doxycycline was also tested to determine whether it could decrease the severity or rate of progression of OA in the knee. Results revealed doxycycline to lower the rate of joint space narrowing in women with moderate unilateral knee OA, but had no effect on the rate of joint space narrowing in contralateral knee (63).

    Asthma

    Two clinical trials are listed as complete in the ClinicalTrials.gov portal. Both the clinical trials examined the add-on effects of minocycline to standard asthma care regimen in adults with asthma (NCT00456677,NCT00536042). The results are not yet available. It is noteworthy that tetracycline, especially minocycline, in addition to its potent anti-inflammatory effects also decreases the production of IgE in an isotype-specific manner and suppresses the IgE-mediated responses (64).

    Chronic obstructive pulmonary disease (COPD)

    Based on the observation that doxycycline inhibits neutrophil-mediated inflammation, one clinical trial was performed to examine whether doxycycline reduces the neutrophilic airway inflammation in patients with COPD. Results revealed that doxycycline does not influence the markers of neutrophil inflammation in COPD (65).

    Autism

    Autism is a neurodevelopmental disorder that results in abnormalities concerning social and language development. Although there exists a strong evidence of heritability, the genes involved have not been identified. Based on the observation that minocycline is a powerful inhibitor of microglial activation and is neuroprotective in mouse models of amyotrophic lateral sclerosis and Huntington's disease, 3 clinical trials have been conducted to examine the effectiveness of minocycline in treating regressive autism. In a clinical trial involving a small group of children, no improvements were observed during or after 6 months of minocycline administration (66). Two other clinical trials are currently ongoing (NCT03117530,NCT04031755).

    AD

    Based on the observation that inflammatory responses and microglial activation are involved in the progression of AD, one clinical trial was registered and performed to examine whether combination therapy with doxycycline and rifampicin is useful for treating AD. Results revealed that a 3-month course of doxycycline and rifampicin reduces the cognitive worsening at 6 months of follow-up in patients with mild to moderate AD (67). Because rifampicin also exerts protective effects in various models of neurodegeneration and brain trauma (68), greater number of studies is required to conclude that minocycline has a therapeutic value in the treatment of AD.

    Cystic fibrosis (CF)

    CF is characterized by chronic neutrophilic inflammation and elevated MMP-9 expression in the airway tissues. One clinical trial determined the therapeutic potential of doxycycline in modulating the host airway inflammation in patients with CF and also assessed its pharmacokinetics, pharmacodynamics, and safety. Results primarily revealed the oral absorption characteristics and pharmacokinetic profiles of doxycycline without any description on the therapeutic efficacy (69). Another clinical trial examined the therapeutic value of doxycycline in the treatment of hospitalized CF patients. In this case, the study results showed that doxycycline, administered over an 8-day period during hospitalization, reduces the total sputum MMP-9 levels and improves the clinical outcome measures during CF inpatient exacerbation (70).

    Graves' orbitopathy (GO)

    GO, also called Graves' ophthalmopathy, is an autoimmune disease of the retroocular tissues occurring in patients with Graves' disease. At least 3 clinical trials have been registered in the ClinicalTrials.gov portal. These studies evaluated the effects of a subantimicrobial dose of doxycycline (50 mg/day) in patients with active and moderate-to-severe GO. One clinical trial reported the subantimicrobial dose of doxycycline to be effective and safe for the treatment of active and moderate-to-severe GO (71).

    Type 2 diabetes

    Obesity has been recognized as a state of subclinical inflammation that results in loss of insulin receptor function and decreased insulin sensitivity. As a part of inflammation, expression levels and activity of MMPs are significantly elevated in the rodent models of obesity and obese humans. One clinical trial was performed to test the hypothesis that doxycycline enhances the insulin sensitivity and decreases the inflammation in obese people with type 2 diabetes. Results revealed that short-term treatment with doxycycline decreased inflammation and improved the insulin sensitivity in the type 2 diabetes patients (72). Since this study is a proof-of-concept clinical trial involving a small number of participants, greater number of studies with larger sample sizes is required to determine the therapeutic efficacy of doxycycline in treatment of type 2 diabetes.

    CONCLUSION AND PERSPECTIVES

    Tetracyclines, especially minocycline and doxycycline, are promising candidates for the treatment of diseases with inflammatory background. Tetracyclines are also beneficial in the treatment of autoimmune diseases, such as MA, RA, and asthma. These therapeutic efficacies of tetracyclines are independent of their antimicrobial activities. The quest is to identify the molecular targets for these nonantibiotic activities of tetracyclines; however, the precise molecular target remains to be clarified. Unlike the antimicrobial activity, multiple mechanisms have been proposed for the nonantibiotic activity of tetracyclines, including inhibition of the production of proinflammatory cytokines, inhibition of proinflammatory enzymes such as iNOS and MMPs, downregulation of MHC class II expression in microglia and macrophages, suppression of T cell proliferation and activation, and induction of tolerogenic DCs. The molecular targets for most of these activities have not been clarified yet, except for the binding of tetracyclines to iNOS and MMPs. Hence, future studies should consider elucidating the precise primary target for the nonantibiotic activities of tetracyclines to substantiate the clinically relevant therapeutic effects.

    Notes

    Conflict of Interest:The authors declare no potential conflicts of interest.

    Author Contributions:

    • Conceptualization: Park CS, Kim SH, Lee CK.

    • Formal analysis: Park CS, Kim SH, Lee CK.

    • Project administration: Lee CK.

    • Writing - original draft: Park CS.

    • Writing - review & editing: Park CS, Kim SH, Lee CK.

    Abbreviations

    AD Alzheimer's disease
    APC Ag presenting cell
    CF cystic fibrosis
    COPD chronic obstructive pulmonary disease
    COX-2 cyclooxygenase-2
    DC dendritic cell
    DTH delayed-type hypersensitivity
    EAE experimental autoimmune encephalitis
    GO Graves' orbitopathy
    iNOS inducible nitric oxide synthase
    Mino-DC DC generated from bone marrow cells in the presence of minocycline
    MMP matrix metalloproteinase
    MS multiple sclerosis
    NO nitric oxide
    OA osteoarthritis
    PGE2 prostaglandin E2
    PLA2 phospholipase A2
    RA rheumatoid arthritis
    RRMS relapsing remitting multiple sclerosis
    SRBC sheep red blood cell

    ACKNOWLEDGEMENTS

    This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2020R1A2C1009484, MRC-2017R1A5A2015541).

    References

      1. Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 2001;65:232–260.
      1. Saleha T, Syed Faheem AR, Ummar A. Tetracycline: classification, structure activity relationship and mechanism of action as a theranostic agent for infectious lesions-a mini review. Biomed J Sci Tech Res 2018;7:5787–5796.
      1. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol 2004;3:744–751.
      1. Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res 2009;196:168–179.
      1. Santa-Cecília FV, Leite CA, Del-Bel E, Raisman-Vozari R. The neuroprotective effect of doxycycline on neurodegenerative diseases. Neurotox Res 2019;35:981–986.
      1. Bahrami F, Morris DL, Pourgholami MH. Tetracyclines: drugs with huge therapeutic potential. Mini Rev Med Chem 2012;12:44–52.
      1. Garrido-Mesa N, Zarzuelo A, Gálvez J. What is behind the non-antibiotic properties of minocycline? Pharmacol Res 2013;67:18–30.
      1. Henehan M, Montuno M, De Benedetto A. Doxycycline as an anti-inflammatory agent: updates in dermatology. J Eur Acad Dermatol Venereol 2017;31:1800–1808.
      1. Ali I, Alfarouk KO, Reshkin SJ, Ibrahim ME. Doxycycline as potential anti-cancer agent. Anticancer Agents Med Chem 2017;17:1617–1623.
      1. Giuliani F, Hader W, Yong VW. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. J Leukoc Biol 2005;78:135–143.
      1. Leite LM, Carvalho AG, Ferreira PL, Pessoa IX, Gonçalves DO, Lopes Ade A, Góes JG, Alves VC, Leal LK, Brito GA, et al. Anti-inflammatory properties of doxycycline and minocycline in experimental models: an in vivo and in vitro comparative study. Inflammopharmacology 2011;19:99–110.
      1. Ataie-Kachoie P, Morris DL, Pourgholami MH. Minocycline suppresses interleukine-6, its receptor system and signaling pathways and impairs migration, invasion and adhesion capacity of ovarian cancer cells: in vitro and in vivo studies. PLoS One 2013;8:e60817
      1. Machado LS, Kozak A, Ergul A, Hess DC, Borlongan CV, Fagan SC. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci 2006;7:56.
      1. Hahn JN, Kaushik DK, Mishra MK, Wang J, Silva C, Yong VW. Impact of minocycline on extracellular matrix metalloproteinase inducer, a factor implicated in multiple sclerosis immunopathogenesis. J Immunol 2016;197:3850–3860.
      1. Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID. Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/betaII. J Biol Chem 2007;282:15208–15216.
      1. Kloppenburg M, Brinkman BM, de Rooij-Dijk HH, Miltenburg AM, Daha MR, Breedveld FC, Dijkmans BA, Verweij C. The tetracycline derivative minocycline differentially affects cytokine production by monocytes and T lymphocytes. Antimicrob Agents Chemother 1996;40:934–940.
      1. Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID. Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 2002;51:215–223.
      1. Kim N, Park CS, Im SA, Kim JW, Lee JH, Park YJ, Song S, Lee CK. Minocycline promotes the generation of dendritic cells with regulatory properties. Oncotarget 2016;7:52818–52831.
      1. Lee JH, Park CS, Jang S, Kim JW, Kim SH, Song S, Kim K, Lee CK. Tolerogenic dendritic cells are efficiently generated using minocycline and dexamethasone. Sci Rep 2017;7:15087.
      1. Thong YH, Ferrante A. Effect of tetracycline treatment on immunological responses in mice. Clin Exp Immunol 1980;39:728–732.
      1. Ingham E, Turnbull L, Kearney JN. The effects of minocycline and tetracycline on the mitotic response of human peripheral blood-lymphocytes. J Antimicrob Chemother 1991;27:607–617.
      1. Kloppenburg M, Verweij CL, Miltenburg AM, Verhoeven AJ, Daha MR, Dijkmans BA, Breedveld FC. The influence of tetracyclines on T cell activation. Clin Exp Immunol 1995;102:635–641.
      1. Szeto GL, Pomerantz JL, Graham DR, Clements JE. Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells. J Biol Chem 2011;286:11275–11282.
      1. Kalish RS, Koujak S. Minocycline inhibits antigen processing for presentation to human T cells: additive inhibition with chloroquine at therapeutic concentrations. Clin Immunol 2004;113:270–277.
      1. Clark WM, Lessov N, Lauten JD, Hazel K. Doxycycline treatment reduces ischemic brain damage in transient middle cerebral artery occlusion in the rat. J Mol Neurosci 1997;9:103–108.
      1. Yrjänheikki J, Keinänen R, Pellikka M, Hökfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A 1998;95:15769–15774.
      1. Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002;125:1297–1308.
      1. He Y, Appel S, Le W. Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 2001;909:187–193.
      1. Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002;22:1763–1771.
      1. Mei XP, Xu H, Xie C, Ren J, Zhou Y, Zhang H, Xu LX. Post-injury administration of minocycline: an effective treatment for nerve-injury induced neuropathic pain. Neurosci Res 2011;70:305–312.
      1. Kielian T, Esen N, Liu S, Phulwani NK, Syed MM, Phillips N, Nishina K, Cheung AL, Schwartzman JD, Ruhe JJ. Minocycline modulates neuroinflammation independently of its antimicrobial activity in Staphylococcus aureus-induced brain abscess. Am J Pathol 2007;171:1199–1214.
      1. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci 2001;21:2580–2588.
      1. Cazalis J, Bodet C, Gagnon G, Grenier D. Doxycycline reduces lipopolysaccharide-induced inflammatory mediator secretion in macrophage and ex vivo human whole blood models. J Periodontol 2008;79:1762–1768.
      1. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W. Minocycline as a neuroprotective agent. Neuroscientist 2005;11:308–322.
      1. Bernardino AL, Kaushal D, Philipp MT. The antibiotics doxycycline and minocycline inhibit the inflammatory responses to the Lyme disease spirochete Borrelia burgdorferi . J Infect Dis 2009;199:1379–1388.
      1. Jantzie LL, Todd KG. Doxycycline inhibits proinflammatory cytokines but not acute cerebral cytogenesis after hypoxia-ischemia in neonatal rats. J Psychiatry Neurosci 2010;35:20–32.
      1. Patel A, Khande H, Periasamy H, Mokale S. Immunomodulatory effect of doxycycline ameliorates systemic and pulmonary inflammation in a murine polymicrobial sepsis model. Inflammation 2020;43:1035–1043.
      1. Castro JE, Vado-Solis I, Perez-Osorio C, Fredeking TM. Modulation of cytokine and cytokine receptor/antagonist by treatment with doxycycline and tetracycline in patients with dengue fever. Clin Dev Immunol 2011;2011:370872
      1. Golub LM, Lee HM, Lehrer G, Nemiroff A, McNamara TF, Kaplan R, Ramamurthy NS. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action. J Periodontal Res 1983;18:516–526.
      1. Golub LM, Evans RT, McNamara TF, Lee HM, Ramamurthy NS. A non-antimicrobial tetracycline inhibits gingival matrix metalloproteinases and bone loss in Porphyromonas gingivalis-induced periodontitis in rats. Ann N Y Acad Sci 1994;732:96–111.
      1. Smith GN Jr, Mickler EA, Hasty KA, Brandt KD. Specificity of inhibition of matrix metalloproteinase activity by doxycycline: relationship to structure of the enzyme. Arthritis Rheum 1999;42:1140–1146.
      1. Wang X, Khalil RA. Matrix metalloproteinases, vascular remodeling, and vascular disease. Adv Pharmacol 2018;81:241–330.
      1. Kim YS, Joh TH. Matrix metalloproteinases, new insights into the understanding of neurodegenerative disorders. Biomol Ther (Seoul) 2012;20:133–143.
      1. Baugh MD, Perry MJ, Hollander AP, Davies DR, Cross SS, Lobo AJ, Taylor CJ, Evans GS. Matrix metalloproteinase levels are elevated in inflammatory bowel disease. Gastroenterology 1999;117:814–822.
      1. Niimi N, Kohyama K, Matsumoto Y. Minocycline suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases. Neuropathology 2013;33:612–620.
      1. Schmidt HH, Walter U. NO at work. Cell 1994;78:919–925.
      1. Sakurai H, Kohsaka H, Liu MF, Higashiyama H, Hirata Y, Kanno K, Saito I, Miyasaka N. Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest 1995;96:2357–2363.
      1. Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, Patel IR, Abramson SB. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci U S A 1996;93:14014–14019.
      1. D'Agostino P, Arcoleo F, Barbera C, Di Bella G, La Rosa M, Misiano G, Milano S, Brai M, Cammarata G, Feo S, et al. Tetracycline inhibits the nitric oxide synthase activity induced by endotoxin in cultured murine macrophages. Eur J Pharmacol 1998;346:283–290.
      1. Huang TY, Chu HC, Lin YL, Lin CK, Hsieh TY, Chang WK, Chao YC, Liao CL. Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases. Toxicol Appl Pharmacol 2009;237:69–82.
      1. Pruzanski W, Greenwald RA, Street IP, Laliberte F, Stefanski E, Vadas P. Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol 1992;44:1165–1170.
      1. Dalm D, Palm GJ, Aleksandrov A, Simonson T, Hinrichs W. Nonantibiotic properties of tetracyclines: structural basis for inhibition of secretory phospholipase A2. J Mol Biol 2010;398:83–96.
      1. Hsieh CT, Lee YJ, Dai X, Ojeda NB, Lee HJ, Tien LT, Fan LW. Systemic lipopolysaccharide-induced pain sensitivity and spinal inflammation were reduced by minocycline in neonatal rats. Int J Mol Sci 2018;19:2947.
      1. Attur MG, Patel RN, Patel PD, Abramson SB, Amin AR. Tetracycline up-regulates COX-2 expression and prostaglandin E2 production independent of its effect on nitric oxide. J Immunol 1999;162:3160–3167.
      1. Metz LM, Li D, Traboulsee A, Myles ML, Duquette P, Godin J, Constantin M, Yong VW. GA/minocycline study investigators. Glatiramer acetate in combination with minocycline in patients with relapsing--remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial. Mult Scler 2009;15:1183–1194.
      1. Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G, Greenfield J, Riddehough A, Yeung M, Kremenchutzky M, et al. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med 2017;376:2122–2133.
      1. Minagar A, Alexander JS, Schwendimann RN, Kelley RE, Gonzalez-Toledo E, Jimenez JJ, Mauro L, Jy W, Smith SJ. Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: an open-label trial. Arch Neurol 2008;65:199–204.
      1. Mazdeh M, Mobaien AR. Efficacy of doxycycline as add-on to interferon beta-1a in treatment of multiple sclerosis. Iran J Neurol 2012;11:70–73.
      1. Kloppenburg M, Breedveld FC, Terwiel JP, Mallee C, Dijkmans BA. Minocycline in active rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheum 1994;37:629–636.
      1. O'Dell JR, Blakely KW, Mallek JA, Eckhoff PJ, Leff RD, Wees SJ, Sems KM, Fernandez AM, Palmer WR, Klassen LW, et al. Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine. Arthritis Rheum 2001;44:2235–2241.
      1. Snijders GF, van den Ende CH, van Riel PL, van den Hoogen FH, den Broeder AA, NOAC study groupThe effects of doxycycline on reducing symptoms in knee osteoarthritis: results from a triple-blinded randomised controlled trial. Ann Rheum Dis 2011;70:1191–1196.
      1. O'Dell JR, Elliott JR, Mallek JA, Mikuls TR, Weaver CA, Glickstein S, Blakely KM, Hausch R, Leff RD. Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum 2006;54:621–627.
      1. Brandt KD, Mazzuca SA, Katz BP, Lane KA, Buckwalter KA, Yocum DE, Wolfe F, Schnitzer TJ, Moreland LW, Manzi S, et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum 2005;52:2015–2025.
      1. Joks R, Durkin HG. Effect of tetracyclines on IgE allergic responses and asthma. Recent Pat Inflamm Allergy Drug Discov 2011;5:221–228.
      1. Prins HJ, Daniels JM, Lindeman JH, Lutter R, Boersma WG. Effects of doxycycline on local and systemic inflammation in stable COPD patients, a randomized clinical trial. Respir Med 2016;110:46–52.
      1. Pardo CA, Buckley A, Thurm A, Lee LC, Azhagiri A, Neville DM, Swedo SE. A pilot open-label trial of minocycline in patients with autism and regressive features. J Neurodev Disord 2013;5:9.
      1. Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, Smith S, Borrie M, Decoteau E, Davidson W, et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease. J Am Geriatr Soc 2004;52:381–387.
      1. Yulug B, Hanoglu L, Ozansoy M, Isık D, Kilic U, Kilic E, Schabitz WR. Therapeutic role of rifampicin in Alzheimer's disease. Psychiatry Clin Neurosci 2018;72:152–159.
      1. Beringer PM, Owens H, Nguyen A, Benitez D, Rao A, D'Argenio DZ. Pharmacokinetics of doxycycline in adults with cystic fibrosis. Antimicrob Agents Chemother 2012;56:70–74.
      1. Xu X, Abdalla T, Bratcher PE, Jackson PL, Sabbatini G, Wells JM, Lou XY, Quinn R, Blalock JE, Clancy JP, et al. Doxycycline improves clinical outcomes during cystic fibrosis exacerbations. Eur Respir J 2017;49:1601102
      1. Lin M, Mao Y, Ai S, Liu G, Zhang J, Yan J, Yang H, Li A, Zou Y, Liang D. Efficacy of subantimicrobial dose doxycycline for moderate-to-severe and active Graves' orbitopathy. Int J Endocrinol 2015;2015:285698
      1. Frankwich K, Tibble C, Torres-Gonzalez M, Bonner M, Lefkowitz R, Tyndall M, Schmid-Schönbein GW, Villarreal F, Heller M, Herbst K. Proof of concept: matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes. J Inflamm (Lond) 2012;9:35.
    Cited by
    Crossref 12
    Google Scholar 
    PubMed Central 7
    Web of Science 10
    MeSH Terms
    Anti-Bacterial Agents
    Arthritis, Rheumatoid
    Asthma
    Autoimmune Diseases*
    Bacteria
    Doxycycline
    Exhibition
    Immunotherapy*
    Minocycline
    Models, Animal
    Multiple Sclerosis
    Proteins
    Ribosomes
    Tetracycline
    Tetracyclines*
    Metrics
    Share
    Links to
    Figures
    slide

    1 / 1

    Tables
    slide

    1 / 1

    ORCID IDs
    Funding Information
    PERMALINK