IL-17 induces myocardial fibrosis and enhances RANKL/OPG and MMP/TIMP signaling in isoproterenol-induced heart failure
Introduction
Myocardial fibrosis results from an excessive accumulation of collagen fibers within the myocardium, particularly due to disruption of the equilibrium between the synthesis and degradation of collagen. Previous studies have shown that inflammation and myocardial fibrosis always occur within the same impaired region following cardiomyopathy, hypertension and myocardial infarction. Inflammation is also known to play an important role in myocardial fibrosis (Vanhoutte et al., 2007, Rossi et al., 2003, Wynn, 2004). In the early stages of inflammation, cytokines induce fibrotic cell formation to repair damages. If cytokines continue to exist and stimulate fibrosis following repair, myocardial fibrosis occurs (Martinez Rosas, 2006). Therefore, identifying the cytokines which contribute to myocardial fibrosis is a valuable tool to inhibit and reverse myocardial fibrosis.
Synthesis and degradation of collagen are regulated by matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinase (TIMP). The expressions of MMP and TIMP, and the ratio of MMP/TIMP are elevated when myocardial fibrosis occurs, with the increase in the ratio promoting myocardial fibrosis (Heymans et al., 1999, Romanic et al., 2002, Roten et al., 2000, Sivasubramanian et al., 2001). Cytokines which can affect the MMP/TIMP system may also contribute to myocardial fibrosis. Recent reports have shown that IL-17-induced human colonic subepithelial myofibroblasts, and pancreatic myofibroblasts, and gingival fibroblasts to produce MMP-3 (Bamba et al., 2003, Inatomi et al., 2007, Beklen et al., 2007), and stimulate human cardiac fibroblasts to secrete MMP-1, -2, -3, -9, and -13 (Cortez et al., 2007). Therefore, we hypothesize that IL-17 could be an important stimulatory cytokine in myocardial fibrosis.
Osteoprotegerin (OPG) is a member of the TNF receptor superfamily, which can function as a soluble decoy receptor by binding to the RANK ligand (RANKL) and competitively inhibiting the interaction between RANKL and the receptor of activator of nuclear factor-кB (RANK) (Hofbauer et al., 2000). These factors have been identified as mediators of paracrine signaling in bone metabolism and remodeling (Anderson et al., 1997, Kong et al., 1999). Ueland and Yndestad (2005) reported that myocardial protein levels of OPG, RANK and RANKL, and the ratio of RANKL/OPG were elevated in both experimental and clinical HF. An increased ratio of RANKL/OPG can aggravate myocardial fibrosis; furthermore, the RANKL/OPG system can regulate the MMP/TIMP system (Ueland and Yndestad, 2005, Kartsogiannis et al., 1999), both of which are regulated by IL-17 (Lubberts, 2003). Therefore, we hypothesize that IL-17, a cytokine related with immuno-inflammatory diseases may promote myocardial fibrosis via the RANKL/OPG and MMP/TIMP systems. Neutralization of IL-17 using an anti-IL-17 antibody can potentially inhibit myocardial fibrosis. Furthermore, this hypothesize is supported in immuno-inflammatory myocardial disease briefly (Liu et al., 2008), this study was designed to test it in isoproterenol-induced heart failure (HF).
Section snippets
Animals
56 male Wistar rats (200–250 g) were purchased from the Experimental Animal Center of the First Clinical Hospital of Harbin. All rats used for this study were cared for in accordance with the principles put forth by the experimental animal committee at our university. Rats were housed within individual metabolism cages in an animal facility with a 12 h dark/light cycle and controlled temperature and humidity. Water and food were administered unrestricted throughout the study.
Establishment of the HF model
HF was induced by
Blockade of IL-17 improves myocardial fibrosis and hypertrophy in HF
We used H&E and Masson staining to observe the effect of IL-17 on myocardial fibrosis in isoproterenol-induced heart failure (HF) rats. Isoproterenol activates cardiac sympathic nervous system, and contributes to arrhythmia development and to deterioration of the myocardium, isoproterenol-induced HF is characterized by myocardial fibrosis, cadiocyte swelling and disorder, and inflammatory cells infiltration (Esler and Kaye, 2000). Consistent with this, all three groups showed the above
Discussion
IL-17 is an inflammatory cytokine that consists of six ligands and five receptors. It is produced almost exclusively by activated T cells (termed Th17), a unique T helper cell which is distinct from classic Th1 and Th2 (Aggarwal and Gurney, 2002). In contrast, its receptor is ubiquitously expressed, making almost any cell a potential target of this cytokine. The heart produces low levels of IL-17 at basal conditions (Cortez et al., 2007, Liu et al., 2008), however IL-17 expression increases in
Acknowledgments
This study was supported by grants from the National 973 project, the youth special science and technology foundation in Heilongjiang Province, the Doctoral scientific foundation of the first affiliated hospital of Harbin Medical University (No. 2007033), the focal point item of the science and technology foundation in Heilongjiang Province (ZJY0707-01), the Doctor foundation of the Ministry of Education (No. 20070226005), grants from the scientific and technologic in Heilongjiang Education
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2021, Cellular SignallingCitation Excerpt :The role of Th1 cells in promoting fibrosis seems to be through IFN-γ recruitment of other inflammatory cells, though IFN-γ can also increase expression TNF-α which promotes maturation of pro-fibrotic, M2-like macrophages [59,60]. Th17 cells are essential for the development and progression of cardiac fibrosis [61]. Their expression of IL-17 causes the proliferation of cardiac fibroblasts and, in parallel, induces expression of MMP-1 and MMP-2, both of which cleave fibrillar collagens and aid in turnover of collagens I and III [62].