Increased transcriptional activities of transforming growth factor β receptors in scleroderma fibroblasts
Version of Record online: 27 SEP 2002
Copyright © 2002 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 46, Issue 9, pages 2421–2428, September 2002
How to Cite
Yamane, K., Ihn, H., Kubo, M. and Tamaki, K. (2002), Increased transcriptional activities of transforming growth factor β receptors in scleroderma fibroblasts. Arthritis & Rheumatism, 46: 2421–2428. doi: 10.1002/art.10477
- Issue online: 27 SEP 2002
- Version of Record online: 27 SEP 2002
- Manuscript Accepted: 9 MAY 2002
- Manuscript Received: 18 OCT 2001
- Ministry of Education, Japan. Grant Number: 10770391
- Ministry of Health and Welfare, Japan
- Shiseido Co., Ltd., Japan
To investigate the molecular mechanism of the overexpression of transforming growth factor β receptors (TGFβRs) in dermal fibroblasts from patients with systemic sclerosis (SSc).
Dermal fibroblasts from 7 patients with diffuse SSc of recent onset and from 7 healthy individuals were studied. The expression of TGFβR type I (TGFβRI), TGFβRII, and type I collagen proteins in dermal fibroblasts was determined by immunoblotting. TGFβRI, TGFβRII, and α2(I) collagen messenger RNA (mRNA) were evaluated by Northern blot analysis. The transcriptional activities of the TGFβRI and TGFβRII genes were examined by luciferase assay.
SSc fibroblasts expressed increased levels of TGFβRI and TGFβRII protein and mRNA, as well as increased levels of type I collagen protein and α2(I) collagen mRNA. Moreover, the half-lives of TGFβRI and TGFβRII mRNA in SSc fibroblasts did not change compared with those in control dermal fibroblasts. The promoter activities of the TGFβRI and TGFβRII genes were both significantly increased in SSc fibroblasts compared with those in control fibroblasts. Calphostin C, a specific inhibitor of protein kinase C (PKC), inhibited TGFβRI promoter activity in SSc fibroblasts, and LY294002, an inhibitor of phosphoinositide 3-kinase (PI 3-kinase), inhibited TGFβRII promoter activity in SSc fibroblasts. Moreover, calphostin C and LY294002 inhibited the up-regulation of TGFβRI and TGFβRII mRNA, respectively, in SSc fibroblasts.
These results suggest that increased levels of TGFβRs in SSc fibroblasts play a role in excessive collagen production, and that up-regulation of TGFβR expression might occur at the transcriptional levels. PKC and/or PI 3-kinase might contribute to the up-regulation of TGFβR expression in SSc fibroblasts.