Regulation of PDGFR-alpha in rat pulmonary myofibroblasts by staurosporine

Upregulation of the platelet-derived growth factor (PDGF) receptor-alpha (P DGFR-alpha) is a mechanism of myofibroblast hyperplasia during pulmonary fi brosis. We previously identified interleukin (IL)-1 beta as a major inducer of the PDGFR-alpha in rat pulmonary myofibroblasts in vitro. In this study , we report that staurosporine, a broad-spectrum kinase inhibitor, upregula tes PDGFR-alpha gene expression and protein. A variety of other kinase inhi bitors did not induce PDGFR-alpha expression. Staurosporine did not act via an IL-1 beta autocrine loop because the IL-1 receptor antagonist protein d id not block staurosporine-induced PDGFR-alpha expression. Furthermore, sta urosporine did not activate a variety of signaling molecules that were acti vated by IL-1 beta, including nuclear factor-kappaB, extracellular signal-r egulated kinase, and c-Jun NH2-terminal kinase. However, both staurosporine - and IL-1 beta -induced phosphorylation of p38 mitogen-activated protein k inase and upregulation of PDGFR-alpha by these two agents was inhibited by the p38 inhibitor SB-203580. Finally, staurosporine inhibited basal and PDG F-stimulated mitogenesis over the same concentration range that induced PDG FR-alpha expression. Collectively, these data demonstrate that staurosporin e is a useful tool for elucidating the signaling mechanisms that regulate P DGFR expression in lung connective tissue cells and possibly for evaluating the role of the PDGFR-alpha as a growth arrest-specific gene.