Family members of peroxisome proliferator-activated receptors (PPARs), such as PPARγ, have been shown to be effective in regulating T helper 17 (Th17) cell differentiation. However, whether PPARα, another important family member of PPARs, contributes to Th17 cell differentiation remains controversial. In the present study, we show that PPARα may be a negative regulator of Th17 cell differentiation. In CD4+ T cells from PPARα knockout mice, PPARα deficiency enhances IL-17 and IL-6 levels and promotes Th17 cell differentiation. In contrast, in CD4+ T cells from wild type mice, PPARα activation suppresses Th17 cell differentiation. Furthermore, IL-6 neutralizing antibody dose-dependently reduces the activity of STAT3 and down-regulates the protein expression of RORγt in CD4+ T cells from PPARα knockout mice but has no effect on that of wild type mice. On the other hand, in isolated CD4+ T cells from experimental autoimmune myocarditis (EAM) rats, PPARα agonist Fenofibrate decreased the expression of IL-17 and RORγt, increased the expression of Foxp3, while PPARα antagonist MK886 reversed these effects. Importantly, in vivo activation of PPARα ameliorates EAM by suppressing Th17 cell differentiation through reducing the expression of RORγt and phosphorylated STAT3 that are upregulated in EAM hearts. These results imply that PPARα suppresses Th17 cell differentiation through IL-6/STAT3/RORγt signaling pathway and suggest that PPARα may become a molecular target for treating autoimmune myocarditis.

Prolongation of QRS duration in electrocardiogram is one of the risk factors for morbidity and mortality in many kinds of cardiac diseases. However, its molecular mechanism is unknown. In this study, utilizing experimental autoimmune myocarditis (EAM) as a disease model, we show that the prolongation of QRS duration is accompanied by elevated phosphorylation of connexin 43 (Cx43) at Ser368 (p^S368Cx43). In cultured cells, inflammatory cytokine IL‐1β activates p38 MAPK to up‐regulate p^S368Cx43 and impairs cell‐to‐cell communication. In isolated hearts of normal rats, perfusion of IL‐1β not only increases p^S368Cx43 but also impairs cell‐to‐cell communication and prolongs QRS duration. Furthermore, blockade of p38 MAPK down‐regulates p^S368Cx43, improves cell‐to‐cell communication and reduces QRS duration in EAM. These findings suggest that up‐regulation of p^S368Cx43 by IL‐1β via p38 MAPK contributes to the prolongation of QRS duration and could be a therapeutic target for myocarditis‐induced prolongation of QRS duration.

Effect of PKC inhibitor on experimental autoimmune myocarditis in Lewis rats Effect of PKC inhibitor on experimental autoimmune myocarditis in Lewis rats