title: IL-6-mediated Th17 differentiation through RORγt is essential for the initiation of experimental autoimmune myocarditis.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  To induce EAM, mice were immunized twice with α-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 γt), 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 RORγt locus (RORγt-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 RORγt. 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 RORγt-eGFP homozygous mice, we revealed that RORγt gene ablation conferred the resistance to EAM induction.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Iwakura
authors.forename: Kazuki
authors.initials: K
authors.lastname: Matsui
authors.forename: Haruyo
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Masanori
authors.initials: M
authors.lastname: Obana
authors.forename: Akiko
authors.initials: A
authors.lastname: Hayama
authors.forename: Makiko
authors.initials: M
authors.lastname: Maeda
authors.forename: Yasukatsu
authors.initials: Y
authors.lastname: Izumi
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ohsugi
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology*; D002454:Cell Differentiation; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000209:etiology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D058504:Th17 Cells / Q000166:cytology*
chemical_list: D015850:Interleukin-6; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse