The influence of tetracyclines on T cell activation

Kloppenburg, Margreet; Verweij, C. L.; Miltenburg, A. M. M.; Verhoeven, A. J.; Daha, M. R.; Dijkmans, Ben A. C.; Breedveld, F. C.

doi:10.1111/j.1365-2249.1995.tb03864.x

Cited by 106 publications

(50 citation statements)

References 27 publications

(29 reference statements)

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“…In vitro studies have revealed that minocycline inhibited antigen processing for presentation to human T-cells (Kalish and Koujak, 2004), T-cell proliferation and production of inflammatory cytokines (Kloppenburg et al, 1995;, and T-cell transmigration across a fibronectin matrix barrier, most likely via the inhibition of MMPs. In vivo assays have found that this antibiotic promotes immune differentiation from a type 1 helper T-cell (Th1) to a type 2 helper T-cell (Th2) phenotype, thus modulating the susceptibility to EAE (Popovic et al, 2002).…”

Section: Effects Of Minocycline On Cns Pathologiesmentioning

confidence: 99%

Minocycline: far beyond an antibiotic

Garrido-Mesa

Zarzuelo

Gálvez

2013

British J Pharmacology

778

597

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Minocycline is a second‐generation, semi‐synthetic tetracycline that has been in therapeutic use for over 30 years because of its antibiotic properties against both gram‐positive and gram‐negative bacteria. It is mainly used in the treatment of acne vulgaris and some sexually transmitted diseases. Recently, it has been reported that tetracyclines can exert a variety of biological actions that are independent of their anti‐microbial activity, including anti‐inflammatory and anti‐apoptotic activities, and inhibition of proteolysis, angiogenesis and tumour metastasis. These findings specifically concern to minocycline as it has recently been found to have multiple non‐antibiotic biological effects that are beneficial in experimental models of various diseases with an inflammatory basis, including dermatitis, periodontitis, atherosclerosis and autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease. Of note, minocycline has also emerged as the most effective tetracycline derivative at providing neuroprotection. This effect has been confirmed in experimental models of ischaemia, traumatic brain injury and neuropathic pain, and of several neurodegenerative conditions including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis and spinal cord injury. Moreover, other pre‐clinical studies have shown its ability to inhibit malignant cell growth and activation and replication of human immunodeficiency virus, and to prevent bone resorption. Considering the above‐mentioned findings, this review will cover the most important topics in the pharmacology of minocycline to date, supporting its evaluation as a new therapeutic approach for many of the diseases described herein.

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Section: Effects Of Minocycline On Cns Pathologiesmentioning

confidence: 99%

Minocycline: far beyond an antibiotic

Garrido-Mesa

Zarzuelo

Gálvez

2013

British J Pharmacology

778

597

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“…Multiple immunosuppressive agents target NFAT activation by acting on the phosphatase calcineurin, preventing binding and activation by the Ca 2ϩ -dependent protein calmodulin (25). It has been suggested that the ability of minocycline to suppress T cell proliferation may be related to chelation of Ca 2ϩ , but others were unable to demonstrate that minocycline altered intracellular Ca 2ϩ concentrations (10). We utilized an in vitro phosphatase assay to determine whether the effects of minocycline on NFAT dephosphorylation could be explained by direct chelation of available Ca 2ϩ reducing calcineurin activity or a direct interaction between minocycline and calcineurin, thereby inhibiting its activity (Fig.…”

Section: Minocycline Reduces Transcriptional Activity Of Nfat-mentioning

confidence: 99%

“…In rheumatoid arthritis patients, minocycline significantly improved clinical symptoms and increased the frequency of remissions leading to its usage as a disease modifying anti-rheumatic drug (7)(8)(9). Studies using CD4 ϩ T cell clones derived from the synovium of an rheumatoid arthritis patient showed that minocycline decreased activation-induced proliferation and inflammatory cytokine production (10). Minocycline has also shown therapeutic effects on T cells in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.…”

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confidence: 99%

Minocycline Suppresses Activation of Nuclear Factor of Activated T Cells 1 (NFAT1) in Human CD4+ T Cells

Szeto¹,

Pomerantz

Graham

et al. 2011

Journal of Biological Chemistry

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Minocycline is a tetracycline family antibiotic that has antiinflammatory and immunomodulatory properties. These properties have shown promise in the treatment of conditions such as rheumatoid arthritis, Huntington disease, and multiple sclerosis. As lymphocyte activation is involved in the pathogenesis of many of these diseases, T cells are postulated to be a primary target in minocycline therapy. Previous studies have demonstrated attenuation of CD4 ؉ T cell activation by minocycline, but a specific mechanism has not been elucidated. In this study, we investigated the effect of minocycline on the activity of three key transcription factors regulating CD4 ؉ T cell activation:NF-B, AP-1 (activator protein 1), and NFAT (nuclear factor of activated T) cells. Our data demonstrate that minocycline selectively impairs NFAT-mediated transcriptional activation, a result of increased phosphorylation and reduced nuclear translocation of the isoform NFAT1. Minocycline increased the activity of the NFAT kinase GSK3 and decreased intracellular Ca 2؉ flux, both of which facilitate NFAT1 phosphorylation. These findings provide a novel mechanism for minocycline induced suppression of CD4 ؉ T cell activation and may better inform the application of minocycline as an immunomodulatory agent.The tetracycline family of antibiotics is known to have multiple biological activities distinct from their antimicrobial function. Over the past two decades, the tetracycline derivative minocycline has demonstrated neuroprotective and immunomodulatory effects in animal models of diseases, including multiple sclerosis and Parkinson and Huntington diseases (1-3). Interest in the mechanism of its neuroprotective abilities has driven extensive research on minocycline-induced effects on inflammatory signaling in monocyte lineage cells, particularly the brain-resident microglia (4 -6). Modulation of T cell activation and function has also been proposed as one of the major mechanisms of action of minocycline.T cell activation contributes to disease pathogenesis by creating an inflammatory environment that leads to cellular damage and death as well as decreased immune function. Minocycline has been found to be therapeutic in multiple diseases whose pathogenesis is significantly T cell driven by modulating cellular activation and function. In rheumatoid arthritis patients, minocycline significantly improved clinical symptoms and increased the frequency of remissions leading to its usage as a disease modifying anti-rheumatic drug (7-9). Studies using CD4 ϩ T cell clones derived from the synovium of an rheumatoid arthritis patient showed that minocycline decreased activation-induced proliferation and inflammatory cytokine production (10). Minocycline has also shown therapeutic effects on T cells in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Minocycline treatment of rodents with experimental autoimmune encephalomyelitis attenuated the severity of encephalitis, decreased T cell transmigration in vitro, and reduced CD4...

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“…There are many similarities between the administration of minocycline or anti-EMMPRIN Abs in their ability to modulate T cell activities (1,29,49,50). For example, both minocycline and anti-EMMPRIN Abs reduced T cell proliferation (5,6,12,51,52).…”

Section: Discussionmentioning

confidence: 99%

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Hahn

Kaushik

Mishra

et al. 2016

The Journal of Immunology

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Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial. We investigated whether and how minocycline affects the expression of EMMPRIN on T cells in culture and in mice afflicted with EAE. EMMPRIN expression in cultures of mouse splenocytes or human PBMCs was elevated upon polyclonal T cell activation, and this was reduced by minocycline correspondent with decreased P-Akt levels. An established MS medication, IFN-β, also diminished EMMPRIN levels on human cells whereas this was not readily observed for fingolimod or monomethylfumarate. In EAE-afflicted mice, minocycline treatment significantly reduced EMMPRIN levels on splenic lymphocytes at the presymptomatic (day 7) phase, and prevented the development of disease. Day 7 spleen transcripts from minocycline-treated EAE mice had a significantly lower MMP-9/TIMP-1 ratio, and significantly lower MCT-1 and CD98 levels, factors associated with EMMPRIN function. Day 16 (peak clinical severity) CNS samples from EAE mice had prominent representation of inflammatory perivascular cuffs, inflammatory molecules and EMMPRIN, and these were abrogated by minocycline. Overall, minocycline attenuated the activation-induced elevation of EMMPRIN on T cells in culture and in EAE mice, correspondent with reduced immune function and EAE CNS pathology.

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The influence of tetracyclines on T cell activation

Cited by 106 publications

References 27 publications

Minocycline: far beyond an antibiotic

Minocycline: far beyond an antibiotic

Minocycline Suppresses Activation of Nuclear Factor of Activated T Cells 1 (NFAT1) in Human CD4+ T Cells

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

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