title: p38 MAPK and NF-kappaB mediate COX-2 expression in human airway myocytes.
abstract: 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-kappaB regulation of cyclooxygenase-2 (COX-2) expression in response to a complex inflammatory stimulus consisting of 10 ng/ml interleukin (IL)-1beta, 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 microM) or the proteosome inhibitor MG-132 (1 microM). SB-203580 did not affect cytokine-stimulated IkappaBalpha degradation, NF-kappaB nuclear binding activity, or NF-kappaB-dependent signaling from the COX-2 promoter, indicating that p38 MAPK and NF-kappaB 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-kappaB, participates in the regulation of COX-2 mRNA stability. These findings suggest that although p38 MAPK and NF-kappaB signaling regulate steady-state levels of COX-2 expression, p38 MAPK additionally affects stability of COX-2 mRNA in cytokine-stimulated human airway myocytes.
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada 89557-0046, USA. cas@med.unr.edu
authors.forename: Cherie A
authors.initials: CA
authors.lastname: Singer
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Baker
authors.forename: Alan
authors.initials: A
authors.lastname: McCaffrey
authors.forename: David P
authors.initials: DP
authors.lastname: AuCoin
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Dechert
authors.forename: William T
authors.initials: WT
authors.lastname: Gerthoffer
mesh_terms: D001483:Base Sequence; D001980:Bronchi / Q000201:enzymology*; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000494:pharmacology; D017931:DNA Primers; D004791:Enzyme Inhibitors; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032342:Muscle Cells / Q000201:enzymology; D009130:Muscle, Smooth / Q000201:enzymology; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016207:Cytokines; D017931:DNA Primers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D011725:Pyridines; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580