Role of Nuclear Factor-κB and Mitogen-Activated Protein Kinase Signaling Pathways in IL-1β-Mediated Induction of α-PDGF Receptor Expression in Rat Pulmonary Myofibroblasts

Abstract

AbstractInduction of the α-platelet-derived growth factor receptor (PDGF-Rα) by IL-1β in lung myofibroblasts enhances mitogenic and chemotactic responses to PDGF, and this could be a mechanism of myofibroblast hyperplasia during lung fibrogenesis. Since the regulation of many genes by IL-1β involves activation of NF-κB and mitogen-activated protein (MAP) kinases, we examined these signaling pathways in the control of PDGF-Rα expression by IL-1β in cultured rat lung myofibroblasts. Treatment of cells with pyrrolidine dithiocarbamate (PDTC), an antioxidant that inhibits NF-κB activation, completely blocked PDGF-Rα up-regulation by IL-1β as assayed by [125I]PDGF-AA binding and PDGF-Rα mRNA expression, suggesting a role for NF-κB. However, while IL-1β and TNF-α both induced nuclear binding of the Rel proteins p50 and p65 to an NF-κB consensus oligonucleotide in gel shift assays and caused transient degradation of inhibitor of NF-κB-α (IκB-α) in the cytoplasm of myofibroblasts, only IL-1β up-regulated PDGF-Rα. These results suggest that NF-κB activation alone is not sufficient for up-regulation of PDGF-Rα. An investigation of MAP kinase signaling pathways revealed that IL-1β or PDTC activated extracellular signal-regulated kinase-2 (ERK-2) and c-jun NH2 terminal kinase-1 (JNK-1) phosphorylation of PHAS-1 and c-Jun substrates, respectively. Pretreatment of cells with the MAP kinase kinase-1 (MEK1) inhibitor PD 98059 blocked IL-1β-induced activation of ERK-2 by more than 90% but enhanced IL-1β-stimulated induction of PDGF-Rα expression fourfold. Taken together, these data suggest that IL-1β activates both positive and negative signaling pathways that control the expression of PDGF-Rα. IL-1β appears to mediate its negative effects on PDGF-Rα expression via MAP kinase activation, while the factor(s) that mediate induction of PDGF-Rα remain to be elucidated.