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

Induction of the a-platelet-derived growth factor receptor (PDGF-R alpha) by IL-1 beta 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-1 beta involves activation of NF-kappa B and mitogen-activated protein (MAP) kinases, we examined these signaling pathways in the control of PDGF-R alpha expression by IL-1 beta in cultured rat lung myofibroblasts, Treatment of cells with pyrrolidine dithiocarbamate (PDTC), an antioxidant that inhibits NF-kappa B activation, completely blocked PDGF-R alpha up-regulation by IL-1 beta as assayed by [I-125]PDGF-AA binding and PDGF-R alpha mRNA expression, suggesting a role for NF-kappa B. However, while IL-1 beta and TNF-alpha both induced nuclear binding of the Rel proteins p50 and p65 to an NF-kappa B consensus oligonucleotide in gel shift assays and caused transient degradation of inhibitor of NF-kappa B-alpha (I kappa B-alpha) in the cytoplasm of myofibroblasts, only IL-1 beta upregulated PDGF-R alpha. These results suggest that NF-kappa B activation alone is not sufficient for up-regulation of PDGF-R alpha. An investigation of MAP kinase signaling pathways revealed that IL-1 beta 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-1 beta-induced activation of ERK-2 by more than 90% but enhanced IL-1 beta-stimulated induction of PDGF-R alpha expression fourfold. Taken together, these data suggest that IL-1 beta activates both positive and negative signaling pathways that control the expression of PDGF-R alpha. IL-1 beta appears to mediate its negative effects on PDGF-R alpha expression via MAP kinase activation, while the factor(s) that mediate induction of PDGF-R alpha remain to be elucidated.