IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis

Serada, Satoshi; Fujimoto, Minoru; Mihara, Masahiko; Koike, Nobuo; Ohsugi, Yoshiyuki; Nomura, Shosaku; Yoshida, Hiroto; Nishikawa, Teppei; Terabe, Fumitaka; Ohkawara, Tomoharu; Takahashi, Tsuyoshi; Ripley, Barry; Kimura, Akihiro; Kishimoto, Tadamitsu; Naka, Tetsuji

doi:10.1073/pnas.0802218105

Cited by 308 publications

(284 citation statements)

References 33 publications

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“…In Arid5a −/− mice, both serum levels of IL-6 and TNF-α were dramatically inhibited after EAE induction. A previous report showed that anti-IL-6 antibody inhibited both IL-6 and TNF-α levels in serum after EAE induction (21). Therefore, it is conceivable that chronic elevation of IL-6 level affects TNF-α level more than acute augmentation of IL-6 level by LPS does in vivo.…”

Section: Discussionmentioning

confidence: 98%

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Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo

Masuda

Ripley

Nishimura

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Posttranscriptional regulation of IL-6 has been largely uncharacterized, with the exception of the ribonuclease Regnase-1, which prevents autoimmunity by destabilizing IL-6 mRNA. Here, we identified AT-rich interactive domain-containing protein 5A (Arid5a) as a unique RNA binding protein, which stabilizes IL-6 but not TNF-α mRNA through binding to the 3′ untranslated region 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 LPStreated mice and suppressed IL-6 levels and the development of T H 17 cells in experimental autoimmune encephalomyelitis. 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.immune regulation | RNA-protein complex

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Section: Discussionmentioning

confidence: 98%

“…4B). Inhibition of induction of IL-17-producing T helper cells (T H 17 cells) by reduction of IL-6 level in vivo contributes to suppression of EAE (21). Therefore, we examined whether Arid5a deficiency affects the number of IL-17-producing T cells of CD4 + population after EAE induction.…”

Section: Resultsmentioning

confidence: 99%

Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo

Masuda

Ripley

Nishimura

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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189

254

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“…Studies in various autoimmunity models, such as experimental autoimmune encephalomyelitis (36), uveoretinitis (37), CIA (2,38), and glucose-6-phosphate isomerase-induced arthritis (39), showed that anti-IL-6R antibody treatment suppressed antigen-specific Th17 cell differentiation. In our study, Th17 cell frequencies were not significantly different between tocilizumab responders and nonresponders, and no significant changes were observed throughout the course of CIA in MR16-1-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐6 Receptor Blockade Enhances CD39+ Regulatory T Cell Development in Rheumatoid Arthritis and in Experimental Arthritis

Thiolat

Semerano

Pers

et al. 2014

Arthritis & Rheumatology

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“…For example, IL-6, along with TGF-β, induces Th17 and inhibits TGF-β-induced Treg-cell differentiation [34], and IL-6 deficient mice are EAE resistant [35]. Application of IL-6 receptor mAb [36] ameliorates inflammation in several autoimmune diseases including EAE [37,38]. Also, TNF-α is likely involved in Th17 differentiation [39].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

Hanieh

Abdullah

2013

Eur J Immunol

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MicroRNAs (miRNAs) are a small group of RNAs that are emerging as a new avenue by which autoimmune diseases may be modulated. Accumulating evidence shows that miRNAs are involved in the pathogenesis of MS; however, the interaction of miRNAs with environmentally responsive transcription factors that play prominent roles in MS is unexplored. The activation of aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) alleviates inflammation in experimental autoimmune encephalomyelitis (EAE), the best available model of MS. Therefore, we predicted that TCDD could attenuate EAE by inducing miRNA(s) targeting inflammatory mediators. Here, we show that TCDD induces cholinergic anti-inflammation in EAE mice by upregulating acetylcholinesterasetargeting miR-132. The expression of miR-132 was downregulated in CD4 + cells and associated with EAE severity, while TCDD treatment attenuated EAE by inducing the miR-132/acetylcholinesterase module. Silencing miR-132 in vivo abolished TCDDinduced cholinergic anti-inflammation and aggravated EAE. Overexpression of miR-132 in encephalitogenic CD4 + cells decreased IL-17 and IFN-γ and suppressed T-cell proliferation. In conclusion, our findings identify a new miRNA-based mechanism through which miR-132 mediates TCDD-induced EAE attenuation, suggesting that miR-132 could be a promising therapeutic target for anti-inflammatory treatment of MS.Keywords: Ahr r Cholinergic anti-inflammation r EAE · MicroRNA r miR-132 r TCDD Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor activated by a long list of exogenous ligands including 2,3,7, [1] and 3-methylcholanthrene [2]. Ahr has been shown to mediate the mechanisms that underlie environmental and immunotoxicity [3]. Therefore, Ahr represents a fascinating link between the environment and the immune system. Previously, we and others have Correspondence: Dr. Hanieh Hamza e-mail: hhanieh@kfu.edu.sa demonstrated that Ahr is implicated in the differentiation of Th17/Treg cells [4][5][6], development of autoimmunity [7], and secretion of proinflammatory cytokines [8,9]. Importantly, activation of Ahr has shown a therapeutic potential for autoimmune inflammation. For example, TCDD mitigates CNS inflammation in experimental autoimmune encephalomyelitis (EAE) [5], an established animal model of MS. However, the toxicity of TCDD prohibits its clinical application, and therefore, mechanistic explanation of TCDD-attenuated inflammation may open intriguing possibilities for applicable treatment of MS in human.The microRNAs (miRNAs) are small endogenous noncoding RNAs of ∼22 nt that post-transcriptionally regulate gene expression. These molecules are implicated in different aspects of C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Hanieh Hamza and Alzahrani AbdullahEur. J. Immunol. 2013Immunol. . 43: 2771Immunol. -2782 inflammation. For instance, miR-155, miR-146a, a...

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IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis

Abstract: autoimmunity ͉ multiple sclerosis ͉ T cells

Cited by 308 publications

References 33 publications

Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo

Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo

Interleukin‐6 Receptor Blockade Enhances CD39+ Regulatory T Cell Development in Rheumatoid Arthritis and in Experimental Arthritis

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

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