Antifibrotic effects of hepatocyte growth factor on scleroderma fibroblasts and analysis of its mechanism.
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.
Sherriff-Tadano
Ryoko
R
Graduate School of Medical Science, Saga Medical School, Saga, Japan.
Ohta
Akihide
A
Morito
Fumitaka
F
Mitamura
Mio
M
Haruta
Yoshio
Y
Koarada
Shuichi
S
Tada
Yoshifumi
Y
Nagasawa
Kohei
K
Ozaki
Iwata
I
D019138:Antibodies, Blocking / Q000494:pharmacology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045743:Scleroderma, Diffuse / Q000473:pathology*; D045745:Scleroderma, Limited / Q000473:pathology*; D012867:Skin / Q000473:pathology*
D019138:Antibodies, Blocking; C526317:CCN2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016207:Cytokines; C494041:ETS1 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D055513:Connective Tissue Growth Factor; D017228:Hepatocyte Growth Factor; D003094:Collagen; D020781:Matrix Metalloproteinase 1