title: Mechanisms of cytokine effects on G protein-coupled receptor-mediated signaling in airway smooth muscle.
abstract: Numerous in vitro and in vivo studies have implicated the cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) as mediators of airway inflammation and therefore potentially important substances in the pathogenesis of asthma. In this study, we examined the mechanisms by which IL-1 beta and TNF-alpha affect inhibition of cell growth, G protein-coupled receptor (GPCR) desensitization, and the recently reported adenylyl cyclase sensitization in human airway smooth muscle (HASM) cultures. Our findings demonstrate that adenylyl cyclase sensitization is independent of cytokine-mediated cyclooxygenase type 2 (COX-2) and prostaglandin E(2) (PGE(2)) induction, whereas COX-2 induction appears to be required for both growth inhibition and GPCR desensitization. However, GPCR desensitization was highly dependent on the presence of EGF during chronic treatment with cytokines, which could be explained by a synergistic effect of EGF on cytokine-mediated COX-2 and PGE(2) induction. Interestingly, various agents (including inhibitors of p42/p44 and p38 mitogen-activated protein kinase signaling) were significantly more effective in inhibiting cytokine-mediated PGE(2) induction, GPCR desensitization, and cell growth inhibition than in inhibiting COX-2 induction. These data demonstrate disparity in the requirement and sufficiency of COX-2 induction in promoting different functional effects of IL-1 beta and TNF-alpha in HASM.
authors.affiliation: Division of Critical Care, Pulmonary, Allergic, and Immunological Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
authors.forename: R M
authors.initials: RM
authors.lastname: Pascual
authors.forename: C K
authors.initials: CK
authors.lastname: Billington
authors.forename: I P
authors.initials: IP
authors.lastname: Hall
authors.forename: R A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: J E
authors.initials: JE
authors.lastname: Fish
authors.forename: S P
authors.initials: SP
authors.lastname: Peters
authors.forename: R B
authors.initials: RB
authors.lastname: Penn
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D014132:Trachea / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D009570:Nitriles; D011725:Pyridines; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; C093642:SB 203580