IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway

Abstract

Myocarditis is a common clinical cardiovascular disease, and some patients progress to dilated cardiomyopathy (DCM) with chronic heart failure. Common viral infections are the most frequent cause of myocarditis, but other pathogens and autoimmune diseases have also been implicated. T(h)17 cells are novel IL-17-producing effector T helper cells that play an important role in the development of autoimmune myocarditis. Furthermore, IL-17 is also important in post-myocarditis cardiac remodeling and progression to DCM. However, the mechanisms whereby IL-17 and IL-17-producing cells promote the progression of cardiac fibrosis remain unclear. We therefore investigated whether IL-17 directly induced cardiac fibrosis in experimental autoimmune myocarditis (EAM) and explored the possible molecular mechanisms. The EAM model was induced and serum IL-17 level was detected by ELISA; western blot, immunofluorescence and sirius red staining were used to analyze the collagen expression. PCR was used to assay the IL-17RA and IL-17RC. The results indicated that IL-17 induced cardiac fibrosis both in vitro and in vivo. The protein kinase C (PKC)β/Erk1/2/NF-κB (Nuclear Factor κappa B) pathway was involved in the development of myocardial fibrosis and IL-17 contributed to cardiac fibrosis following EAM via this pathway. These results provide the first direct evidence for the involvement of the PKCβ/Erk1/2/NF-κB signaling pathway in IL-17-induced myocardial fibrosis.

Interleukin-2/Anti-Interleukin-2 Immune Complex Expands Regulatory T Cells and Reduces Angiotensin II-Induced Aortic Stiffening

“…IL-17 has been demonstrated to activate fibroblast proliferation via an Akt/miR-101/MKP-1-dependent p38 MAPK and ERK1/2 pathway [22] and fibrosis through the PKC β /Erk1/2/NF- κ B signaling pathway [23]. It was shown that the fibroblasts constitutively express the IL-17 receptor and IL-17A stimulates fibroblast proliferation and migration [22].…”

Statins as a New Therapeutic Perspective in Myocarditis and Postmyocarditis Dilated Cardiomyopathy

“…Moreover, treatment of BALB/c mice with anti-IL17A monoclonal antibody administered after the onset of EAM abrogated myocarditis-induced cardiac fibrosis and preserved ventricular function [5]. These observations, together with the evidence that IL-17A is able to directly signal the function of the cardiac fibroblast [25][26][27], indicate that this cytokine critically contributes to myocardial fibrosis and remodelling of the extracellular matrix, thus driving the progression to DCM.…”

Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction

“…In addition to the hypertrophic and fibrotic responses by the classical pro-inflammatory cytokines, IL-17 also induces cardiac inflammation, hypertrophy, and fibrosis (46,47). TRAF3IP2 is a critical intermediate in IL-17 signaling (11,12).…”

“…It induces cardiac fibroblast proliferation and migration via p38 MAPK and ERK1/2 activation and MKP-1 (mitogen-activated protein kinase phosphatase-1) inactivation (48). On the other hand, its gene deletion inhibits the onset of myocarditis and progression to inflammatory dilated cardiomyopathy (47). Furthermore, macrophage/ monocyte-derived IL-17A may induce TNF-␣, IL-1␤, MCP-1, and MMPs, which play a role in adverse cardiac remodeling (49).…”