Antifibrotic effects of hepatocyte growth factor on scleroderma fibroblasts and analysis of its mechanism

Abstract

We investigated the effect of hepatocyte growth factor (HGF) on collagen metabolism in cultured fibroblasts from scleroderma (SSc) patients and discussed the possible mechanism of its effect. Synthesis of matrix metalloproteinase-1 (MMP-1) and collagen and mRNA levels of various cytokines were examined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction, respectively. Hepatocyte growth factor enhanced MMP-1 production and mRNA levels of MMP-1 and Ets-1 (a transcriptional factor of MMPs). In addition, HGF suppressed collagen synthesis and mRNA levels of procollagenalpha1(I) and connective tissue growth factor (CTGF) in SSc fibroblasts. Expression of transforming growth factor (TGF)-beta1 was not inhibited significantly in SSc or control fibroblasts. Hepatocyte growth factor also increased interferon (IFN)-gamma mRNA significantly in SSc and control fibroblasts. Addition of anti-HGF antibody neutralized these effects of HGF on MMP-1 and collagen synthesis. The results suggest that HGF can suppress collagen accumulation in SSc fibroblasts by increasing MMP-1 levels possibly via activation of Ets-1 and also by decreasing collagen synthesis, which may be partly related to inhibition of CTGF, and increasing IFN-gamma levels rather than the effect on TGF-beta1. The present study indicates that HGF may be a promising therapeutic agent for this intractable disease.

IL-18 Downregulates Collagen Production in Human Dermal Fibroblasts via the ERK Pathway

“…Recently, Ets-1 has been shown to modulate the transcription of ECM genes, including type I collagen (CzuwaraLadykowska et al, 2002;Sherriff-Tadano et al, 2006). Constitutive expression of Ets proteins has been associated with cellular transformation of erythroblasts and fibroblasts (Kola et al, 1993;Iwasaka et al, 1996;Reisdorff et al, 2002).…”

“…Several potential binding sites for transcription factors, such as members of the Ets family, are located in the collagen promoter, and it is thought that these factors are associated with collagen gene expression (Znoyko et al, 2006;Peng et al, 2008). Czuwara-Ladykowska et al (2002) reported that elevated expression of Ets-1 altered TGF-b induction of type I collagen and other matrix-related genes in human fibroblasts (Sherriff-Tadano et al, 2006), showing that Ets-1 may act as an antagonist of the profibrotic effect of TGF-b. It is known that overexpression of Ets-1 in cultured mesangial cells suppresses the TGF-b-induced reduction of DNA-binding activity (Mizui et al, 2006).…”

“…Recently, Sherriff-Tadano et al (2006) reported that inhibition of collagen synthesis induced by HGFs was due in part to the enhanced action of IFN-g, an antifibrotic cytokine. We observed that IL-18 inhibited collagen synthesis in SSc dermal fibroblasts.…”

“…Ets-1 is involved in IL-18-regulated collagen expression Collagen genes are regulated by several transcription factors, including Ets-1 (Czuwara-Ladykowska et al, 2002;Mizui et al, 2006;Sherriff-Tadano et al, 2006). To determine whether IL-18 alters collagen expression via regulation of Ets-1, Ets-1 levels were compared under different stimulation conditions.…”

New molecular medicine-based scar management strategies

“…It has been suggested that HGF (hepatocyte growth factor) exerts antifibrotic effects, via the c-met receptor and TGF-β1 inhibition [96], or through peroxisome proliferator-activated receptor- (PPAR)γ agonists [97], among other mechanisms, dependently or independently of TGF-β [98, 99]. It has been shown that local administration of HGF gene enhances the regeneration of dermis and minimizes scarring in acute incisional wounds in an experimental model [100].…”