Role of nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways in IL-1 beta-mediated induction of alpha-PDGF receptor expression in rat pulmonary myofibroblasts.
Induction of the alpha-platelet-derived growth factor receptor (PDGF-Ralpha) by IL-1beta 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-1beta involves activation of NF-kappaB and mitogen-activated protein (MAP) kinases, we examined these signaling pathways in the control of PDGF-Ralpha expression by IL-1beta in cultured rat lung myofibroblasts. Treatment of cells with pyrrolidine dithiocarbamate (PDTC), an antioxidant that inhibits NF-kappaB activation, completely blocked PDGF-Ralpha up-regulation by IL-1beta as assayed by [125I]PDGF-AA binding and PDGF-Ralpha mRNA expression, suggesting a role for NF-kappaB. However, while IL-1beta and TNF-alpha both induced nuclear binding of the Rel proteins p50 and p65 to an NF-kappaB consensus oligonucleotide in gel shift assays and caused transient degradation of inhibitor of NF-kappaB-alpha (IkappaB-alpha) in the cytoplasm of myofibroblasts, only IL-1beta upregulated PDGF-Ralpha. These results suggest that NF-kappaB activation alone is not sufficient for up-regulation of PDGF-Ralpha. An investigation of MAP kinase signaling pathways revealed that IL-1beta 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-1beta-induced activation of ERK-2 by more than 90% but enhanced IL-1beta-stimulated induction of PDGF-Ralpha expression fourfold. Taken together, these data suggest that IL-1beta activates both positive and negative signaling pathways that control the expression of PDGF-Ralpha. IL-1beta appears to mediate its negative effects on PDGF-Ralpha expression via MAP kinase activation, while the factor(s) that mediate induction of PDGF-Ralpha remain to be elucidated.
Airway Inflammation Section, Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
P M
PM
Lindroos
A B
AB
Rice
Y Z
YZ
Wang
J C
JC
Bonner
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000187:drug effects; D015398:Signal Transduction / Q000276:immunology*; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D005419:Flavonoids; D007375:Interleukin-1; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C020972:pyrrolidine dithiocarbamic acid; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017479:Receptors, Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one