| First Author | Yamashita T | Year | 2011 |
| Journal | Cardiovasc Res | Volume | 91 |
| Issue | 4 | Pages | 640-8 |
| PubMed ID | 21622681 | Mgi Jnum | J:191625 |
| Mgi Id | MGI:5462176 | Doi | 10.1093/cvr/cvr148 |
| Citation | Yamashita T, et al. (2011) IL-6-mediated Th17 differentiation through RORgammat is essential for the initiation of experimental autoimmune myocarditis. Cardiovasc Res 91(4):640-8 |
| abstractText | AIMS: Interleukin (IL)-17-producing helper T (Th17) cells have been proposed to participate in the pathogenesis of chronic inflammation, such as autoimmune myocarditis. IL-6 gene ablation confers the resistance to experimental autoimmune myocarditis (EAM). In this study, we have addressed the pathological roles of IL-6 in the regulation of Th17 cells in EAM. METHODS AND RESULTS: To induce EAM, mice were immunized twice with alpha-myosin heavy chain peptide. Three weeks after the first injection, the cardiac expression of the Th17-specific transcription factor, retinoic acid receptor-related orphan nuclear receptor (ROR gammat), was up-regulated. Consistently, Th17 cells were recruited into EAM hearts, as analysed by flow cytometry. Using the mice with enhanced green fluorescence protein (eGFP) gene knocked-in at RORgammat locus (RORgammat-eGFP mice), we observed Th17 cell infiltration into inflamed lesions. Pre-treatment with IL-6 receptor (IL-6R)-blocking antibody (anti-IL-6R Ab) inhibited EAM induction in terms of disease severity score (3.5 +/- 0.8; IgG vs. 0.5 +/- 0.8; anti-IL-6R Ab, n = 6, P< 0.01) and suppressed the myocardial expression of IL-17 and RORgammat. In contrast, the administration of anti-IL-6R Ab 7 days after the first immunization failed to show the inhibitory effects, suggesting that IL-6 plays important roles in EAM initiation. Finally, by generating RORgammat-eGFP homozygous mice, we revealed that RORgammat gene ablation conferred the resistance to EAM induction. CONCLUSION: IL-6-mediated induction of Th17 cells is critical for the onset of EAM, but not for its progression. IL-6/Th17 signalling could be a promising therapeutic target for the prevention of myocardial inflammation. |
