Regulation of interleukin-1beta -induced platelet-derived growth factor receptor-alpha expression in rat pulmonary myofibroblasts by p38 mitogen-activated protein kinase.
The potential role of p38 mitogen-activated protein (MAP) kinase in platelet-derived growth factor receptor-alpha (PDGF-Ralpha) gene expression was investigated using cultured rat pulmonary myofibroblasts. p38 MAP kinase was constitutively expressed in myofibroblasts and activated by interleukin (IL)-1beta. A pyridinylimidazole compound, SB203580, completely inhibited the ability of p38 MAP kinase activity to phosphorylate PHAS-1 substrate. SB203580 inhibited IL-1beta-induced up-regulation of PDGF-Ralpha mRNA and protein in a concentration-dependent manner. Other kinase inhibitors, including the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor PD98059, did not block up-regulation of PDGF-Ralpha. The IL-1beta-induced increase in the number of (125)I-PDGF-AA-binding sites at the cell surface was reduced >70% by pretreatment with SB203580. Accordingly, an enhancement of PDGF-AA-stimulated DNA synthesis following IL-1beta pretreatment was blocked >70% by SB203580. SB203580 did not affect IL-1beta-induced ERK activation, yet enhanced IL-1beta-induced JNK activation approximately 2-fold. Treatment of cells with SB203580 after inhibition of transcription by actinomycin D decreased the half-life of IL-1beta-induced PDGF-Ralpha mRNA from >4 to approximately 1.5 h. Moreover, pretreatment of cells with cycloheximide blocked induction of PDGF-Ralpha mRNA by IL-1beta, suggesting that de novo protein synthesis was required for PDGF-Ralpha mRNA stabilization. These data indicate that p38 MAP kinase regulates PDGF-Ralpha expression at the translational level by signaling the synthesis of an mRNA-stabilizing protein.
Wang
Y Z
YZ
Laboratory of Pulmonary Pathobiology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Zhang
P
P
Rice
A B
AB
Bonner
J C
JC
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D008168:Lung; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases