Induction of the platelet-derived growth factor alpha-receptor (alpha PDGF-R) by interleukin-1beta (IL-1) is a mechanism for myofibroblast hyperplasia during lung fibrosis. In contrast to IL-1, other mediators including transforming growth factor (TGF)-b1 and prostaglandin-E2 (PGE2) down-regulate alpha PDGF-R and suppress myofibroblast growth. We sought to identify the signal transduction pathways that lead to induction or suppression of alpha PDGF-R. We have demonstrated that the alpha PDGF-R is up-regulated both in vitro in cultured lung myofibroblasts and in vivo during metal-induced pulmonary fibrosis in rats. Induction of this receptor corresponds to an increased growth response of lung myofibroblasts. In vitro, we demonstrated that IL-1 activates all three major mitogen-activated protein (MAP) kinase pathways (ERK, JNK, and p38 MAP kinase). Blocking the activity of p38 MAP kinase significantly inhibited IL-1 induced up-regulation of the alpha PDGF-R. p38 MAP kinase activation following IL-1 treatment of myofibroblasts serves to signal the production of a protein(s) that stabilizes alpha PDGF-R mRNA. The transcription factors downstream of these MAP kinase pathways that regulate of the positive or negative regulatory pathways remains to be elucidated. The alkaloid staurosporine serves as a useful tool to study alpha PDGF-R regulation, as this drug mimics the up-regulatory effect of IL-1 on increasing alpha PDGF-R expression without activating many of the other intracellular signaling pathways that are turned on by IL-1. However, like IL-1, staurosporine-induced up-regulation of alpha PDGF-Ra is dependent on p38 MAP kinase.
