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

Abstract

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...

Comment on “Aneurysmal Lesions of Patients with Abdominal Aortic Aneurysm Contain Clonally Expanded T Cells”

“…Our work sets the stage for identifying the putative agent(s) underlying the process. Doxycycline and/or other tetracyclines also act by arresting T cell proliferation in AAA lesions by inhibiting mitochondrial protein synthesis (8,9) or suppressing NF of activated T cells in human CD41 T cells (10), doxycycline inhibits also monocytes and granulocytes (5,8,9) We agree with Drs. Koon and Taanman that doxycycline may be effective in inhibiting T cells in AAA as well as other autoimmune diseases where clonal expansions of T cells have been demonstrated and should be evaluated further for this purpose.…”

rRNA Binding Sites and the Molecular Mechanism of Action of the Tetracyclines

“…However, the susceptibility of protozoa species which lack mitochondria (e.g., Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica) (7,66), as well as viral pathogens (Table 1), raises further questions about the exact molecular mechanism(s) of action of the tetracy-clines. In contrast to the proffered antiprotozoal activity via mitochondrial and endosymbiont rRNA binding, the antiviral activities of the tetracyclines have not been associated with rRNA binding (2,13,14,(68)(69)(70). Rather, the antiviral activity has been attributed in part to anti-inflammatory (4, 15), antiapoptotic (2), and neuroprotective (1) properties.…”

“…It is possible that minocycline suppresses both viral replication and activation of the inflammatory and cellular responses to these viral infections via an effect on dsRNAs (14). Hence, the antiapoptotic, anti-inflammatory, and antiviral activities of minocycline that have been observed in viral infections (2,13,14,(68)(69)(70) may also be mediated via interactions with dsRNAs. Further investigations in line with the dsRNA binding perspectives are, therefore, quite imperative.…”

Tetracyclines and pain

“…Minocycline and doxycycline reduce NF-κB activity in THP-1 cells stimulated with sonicated Borrelia burgdorferi (Bernardino et al 2009). Moreover, minocycline also inhibits NF-κB activation in microglial cells (Si et al 2004;Nikodemova et al 2006), though this effect has not been observed in human CD4+ T cells (Szeto et al 2011).…”

“…In fact, some molecular targets have been suggested. Recently, Szeto et al (2011) have shown that in human CD4+ T cells, minocycline reduces nuclear factor of activated T-cells 1 (NFAT1) activation, which is a key regulatory factor in T cell activation. This reduction in NFAT1 activation might be due to the increased glycogen synthase kinase-3 activity and attenuation of intracellular Ca 2+ influx induced by minocycline.…”