The discovery of interleukin 6 (IL-6) and elucidation of its associated receptor signaling pathway, highlighted the important role of cytokines in regulating immune cells. When cytokines become aberrantly regulated, this leads to the inappropriate activation of immune cells. In some cases, this is an important step in the development of autoimmune diseases, such as rheumatoid arthritis (activation of IL-6 signaling) and systemic lupus erythematosus (activation of type-I interferon signaling). The current challenges, and principal aims of our research, are to make advances in our understanding of the mechanisms of autoimmune disease and related cytokine signaling pathways, to ultimately improve health care- thus "from bench to bedside".
Post-transcriptional regulation of IL-6 has been largely uncharacterized, with the exception of the RNase Regnase-1, which prevents autoimmunity by destabilizing IL-6 mRNA. Here, we identified a novel RNA binding protein, AT-rich interactive domain 5a (Arid5a), which stabilizes IL-6 but not TNF-α mRNA through binding to the 3' untranslated region (UTR) of IL-6 mRNA. Arid5a was enhanced in macrophages in response to LPS, IL-1β and IL-6. Arid5a deficiency inhibited elevation of IL-6 serum level in LPS-treated mice, and suppressed IL-6 levels and the development of TH17 cells in experimental autoimmune encephalomyelitis (EAE). Importantly, Arid5a inhibited the destabilizing effect of Regnase-1 on IL-6 mRNA. These results indicate that Arid5a plays an important role in promotion of inflammatory processes and autoimmune diseases.
Aryl hydrocarbon receptor (AHR) has critical roles in autoimmune diseases such as multiple sclerosis (MS) by controlling Interleukin 17 (IL-17)-producing T helper cells (TH17 cells) and Regulatory T cells (Treg cells). Although various transcription factors and cytokines have been identified as key participants in TH17 generation, the role of microRNA is poorly understood. We found that miR-132/212 cluster is induced by AHR activation under TH17 -inducing, but not Treg cell-inducing conditions. miR-132/212 cluster deficiency abrogated enhancement of TH17 cell differentiation by AHR activation. We identified Bcl-6, a negative regulator of TH17 cell differentiation, as a potential target of miR-132/212 cluster. We investigated the roles of miR-132/212 cluster in experimental autoimmune encephalomyelitis (EAE), a murine model of MS. miR-132/212 cluster deficient mice showed resistance to the development of EAE and decreased frequency of both TH1 and TH17 cells in draining lymph nodes. Our findings indicate the novel mechanism of AHR-dependent TH17 cell differentiation via miR-132/212 cluster.
Type-I interferon is important for anti-viral immunity, but its over-production is linked to the development of autoimmunity. Type-I interferon production requires the transcription factor IRF7. How type-I interferon signals to attenuate its own production in immune homeostasis is not known. Here we show that type-I interferon induces expression of PPAR-γ, which forms an inhibitory interaction with IRF7, attenuating type-I interferon production via the virus-activated (MyD88-independent) pathways in fibroblasts and TLR-activated (MyD88-dependent) pathways in pDCs, and type-I IFN-dependent responses in autoimmunity. Thus all aspects of the type-I IFN system, its production in innate and adaptive immunity and associated immunopathology, are self-controlled through a two-step process of (i) type-I IFN-induced PPAR-γ expression and (ii) formation of an inhibitory PPAR-γ/IRF7 complex.
Our research is engaged in clinical studies on the effectiveness of anti-IL6R antibody (Tocilizumab) in autoimmune diseases.
Tocilizumab can inhibit bone resorption and joint destruction in chronic rheumatoid arthritis (RA) patients by a large-scale randomized control trial. This effect is due to the inhibitory effect of IL-6 signal blockade on the expression of Rank-ligand and differentiation into osteoclasts of mononuclear cells.
A randomized placebo-controlled phase III trial confirmed that Tocilizumab is effective and safe in patients with systemic-onset juvenile idiopathic arthritis (JIA). The USA and EU approved the use of Tocilizumab for the treatment of JIA. In December 2012, large-scale clinical trials for JIA in Europe and the USA confirmed efficacy and safety of Tocilizumab.
Other autoimmune inflammatory diseases have been treated with Tocilizumab, including refractory relapsing polychondritis, AA amyloidosis, reactive arthritis, polymyalgia rheumatica, systemic sclerosis, polymyositis and acquired hemophilia A. The results confirmed efficacy and safety of Tocilizumab in these diseases.
Interleukin-6: from basic science to medicine--40 years in immunology.