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IL-17 induces myocardial fibrosis and enhances RANKL/OPG and MMP/TIMP signaling in isoproterenol-induced heart failure.

Abstract：

OBJECTIVE:This study was designed to investigate whether IL-17 can regulate the expression of the MMP/TIMP system, the OPG/RANK/RANKL system, or type-I and type-III collagen fibers in a rat model of isoproterenol-induced heart failure (HF). We also investigated the effect of IL-17 on myocardial fibrosis in this model. METHODS:HF was induced in Wistar-Kyoto rats by hypodermic injection of isoproterenol (ISO) twice every 24 h. After 2 months, the surviving rats were divided into three groups: monoclonal Anti-IL-17 Ab (100 microg/day), IgG (100 microg/day) or PBS were injected five times every 48 h (i.p.). One day after the last injection, all of the rats were sacrificed. H&E and Masson staining were used to evaluate myocardial fibrosis, and immunohistochemistry was used to measure the levels of MMP-1, TIMP-1, TIMP-4, OPG, RANKL, type-I and type-III collagen fibers. We also treated adult rat cardiac fibroblasts with IL-17 (10 ng/ml), IL-17 (10 ng/ml)+OPG (10 ng/ml), IL-17 (10 ng/ml)+anti-RANKL Ab (100 ng/ml), or PBS for 24 h, realtime RT-PCR was used to measure the expressions of MMP-1. RESULTS:The expressions of MMP-1, RANKL, and type-I and -III collagen fibers decreased, and the expressions of TIMP-1, TIMP-4, and OPG increased in the Anti-IL-17 group compared to controls. H&E and Masson staining revealed that blockade of IL-17 can improve myocardial fibrosis in HF. IL-17 increased the expression of MMP-1 in cardiac fibroblasts, and OPG and anti-IL-17 Ab could inhibit this function partly. Thus, IL-17 was dependent on the RANKL/OPG system to induce MMP-1 partly. CONCLUSION:Our study demonstrates the contribution of IL-17 to myocardial fibrosis in isoproterenol-induced HF. IL-17 can regulate the RANKL/OPG and MMP/TIMP systems in this model. The RANKL/OPG system is one of intermediaries between IL-17 and MMP-1 in cardiac fibroblasts. As a harmful cytokine, anti-IL-17 treatment is a potential therapeutic strategy in HF.

journal_name

Exp Mol Pathol

journal_title

Experimental and molecular pathology

authors

Feng W,Li W,Liu W,Wang F,Li Y,Yan W

doi

10.1016/j.yexmp.2009.06.001

subject

Has Abstract

pub_date

2009-12-01 00:00:00

pages

212-8

issue

3

eissn

0014-4800

issn

1096-0945

pii

S0014-4800(09)00069-0

journal_volume

87

pub_type

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