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Am J Physiol Lung Cell Mol Physiol 285: L1087-L1098, 2003. First published July 18, 2003; doi:10.1152/ajplung.00409.2002
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p38 MAPK and NF-{kappa}B mediate COX-2 expression in human airway myocytes

Cherie A. Singer,1 Kimberly J. Baker,2 Alan McCaffrey,1 David P. AuCoin,2 Melissa A. Dechert,2 and William T. Gerthoffer1,2

1Department of Pharmacology and 2Cell and Molecular Biology Program, University of Nevada School of Medicine, Reno, Nevada 89557-0046

Submitted 27 November 2002 ; accepted in final form 17 July 2003

We have previously demonstrated that p38 and extracellular signal-regulated protein kinase (ERK) mitogen-activated protein kinases (MAPK) are components of proinflammatory induced cytokine expression in human airway myocytes. The experiments described here further these studies by examining p38 MAPK and NF-{kappa}B regulation of cyclooxygenase-2 (COX-2) expression in response to a complex inflammatory stimulus consisting of 10 ng/ml interleukin (IL)-1{beta}, tumor necrosis factor-{alpha} (TNF-{alpha}), and interferon (IFN)-{gamma}. COX-2 expression was induced with this stimulus in a time-dependent manner, with maximal expression seen 12-20 h after treatment. Semiquantitative RT-PCR and immunoblotting experiments demonstrate decreased COX-2 expression following treatment with the p38 MAPK inhibitor SB-203580 (25 µM) or the proteosome inhibitor MG-132 (1 µM). SB-203580 did not affect cytokine-stimulated I{kappa}B{alpha} degradation, NF-{kappa}B nuclear binding activity, or NF-{kappa}B-dependent signaling from the COX-2 promoter, indicating that p38 MAPK and NF-{kappa}B may affect COX-2 expression via separate signaling pathways. SB-203580, but not MG-132, also increased the initial rate of COX-2 mRNA decay, indicating p38 MAPK, but not NF-{kappa}B, participates in the regulation of COX-2 mRNA stability. These findings suggest that although p38 MAPK and NF-{kappa}B signaling regulate steady-state levels of COX-2 expression, p38 MAPK additionally affects stability of COX-2 mRNA in cytokine-stimulated human airway myocytes.

inflammation; mitogen-activated protein kinase; mRNA stability; cytokines



Address for reprint requests and other correspondence: C. A. Singer, Dept. of Pharmacology/318, Univ. of Nevada School of Medicine, Reno, NV 89557-0046 (E-mail: cas{at}med.unr.edu).




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