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
| Autor: | P M, Lindroos, A B, Rice, Y Z, Wang, J C, Bonner |
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| Rok vydání: | 1998 |
| Předmět: |
Flavonoids
Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Pyrrolidines Receptor Platelet-Derived Growth Factor alpha Tumor Necrosis Factor-alpha JNK Mitogen-Activated Protein Kinases MAP Kinase Kinase 1 NF-kappa B Fibroblasts Protein Serine-Threonine Kinases Protein-Tyrosine Kinases Rats Up-Regulation Enzyme Activation Thiocarbamates Calcium-Calmodulin-Dependent Protein Kinases Animals Receptors Platelet-Derived Growth Factor Mitogen-Activated Protein Kinases Lung Cells Cultured Interleukin-1 Protein Binding Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 161(7) |
| ISSN: | 0022-1767 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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