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. Our most recent work has demonstrated that interleukin-13 (IL-13), a Th2 cytokine implicated in the pathogenesis of asthma and fibrosis, stimulates the growth of lung fibroblasts via a PDGF-AA autocrine loop. Induction of PDGF-AA production by IL-13 is dependent on activation of the STAT-6 transcription factor. These findings could have important implications for our understanding of chronic airway remodeling involved in the pathogenesis of asthma and chronic bronchitis.
