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Originally published In Press as doi:10.1074/jbc.M909785199 on May 11, 2000

J. Biol. Chem., Vol. 275, Issue 29, 22550-22557, July 21, 2000
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Regulation of Interleukin-1beta -induced Platelet-derived Growth Factor Receptor-alpha Expression in Rat Pulmonary Myofibroblasts by p38 Mitogen-activated Protein Kinase*

Yi-Zhe Wang, Ping Zhang, Annette B. Rice, and James C. BonnerDagger

From the Laboratory of Pulmonary Pathobiology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

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 125I-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 ~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.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Laboratory of Pulmonary Pathobiology, NIEHS, P.O. Box 12233, Research Triangle Park, NC 27709. Tel.: 919-541-0766; Fax: 919-541-4133; E-mail: bonnerj@niehs.nih.gov.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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