Fibrohlast proliferation is a key event in several normal processes like tissue repair and the control of abnormal cell proliferation leading tu fibrosis is a primary problem in mimerons diseases. In this study, cAMP level-raising agents were shown to inhibit human lung fibroblast proliferation induced by PDGF (Platelet-derived Growth Factor). We wanted to know at which level of the PDGF-signalling pathways cAMP interferes. The effects of i'DGF arc mediated by the activation of protein kinase cascades leading to the activation of transcription factor-; and gene expression. We first investigated the role of phosphatidylinositol 3-kinase (PI-3K). protein kinase C (PKC) arid mitogenadivated protein kinases (MAPK) in PDGK-indiiced cell proliferation. Wortmannin and staurosporine, inhibitors of respective PI-3K and PKC, had no effect on PDGF-induced cell growth, suggesting that PI-3K and PKC activation is not essential to this fibroblastic response. PDGF didnt affect PKC activity in these cells. PDGF was shown to induce MAPK phosphorylation which is not affected by dibutyryl-cAMP (dbcAMP. analogue of cAMP). In contrast, dbcAMP inhibits AP-1-DNA-binding activity induced by PDGF. A reduction of PDGF-induced c-rnyc and c-jun m-RNA expression was also observed in cells incubated with dbcAMP. However, cibrAMP had no effect on c-fos rnRNA expression. One results indicates that the inhibitrory effect of cAMP on POGF-indnced cell growth may result fron an inhibition of protooncogenes activation and expression.
|Publication status||Published - 1997|