期刊
CARDIOVASCULAR RESEARCH
卷 91, 期 4, 页码 640-648出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvr148
关键词
Interleukin-6; ROR gamma t; Autoimmune myocarditis; Inflammation; Th17
资金
- Japan Society for the Promotion of Science
- Osaka Foundation for Promotion of Clinical Immunology
- Knowledge Cluster Initiative of the Ministry of Education, Culture, Sports, Science and Technology of Japan
- Grants-in-Aid for Scientific Research [21591276, 22591101] Funding Source: KAKEN
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 gamma t), 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 ROR gamma t locus (ROR gamma t-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 ROR gamma t. 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 ROR gamma t-eGFP homozygous mice, we revealed that ROR gamma t 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.
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