title: Regulation of IL-1beta -induced GM-CSF production in human airway smooth muscle cells by carbon monoxide.
abstract: Asthma, a chronic inflammatory disease of the airways, involves the increased expression of inflammatory mediators, including granulocyte-monocyte colony-stimulating factor (GM-CSF). Heme oxygenase-1 (HO-1), a stress-response protein, confers protection against oxidative stress. We hypothesized that carbon monoxide (CO), a byproduct of HO-1-dependent heme catabolism, regulates GM-CSF synthesis in human airway smooth muscle cells (HASMC). IL-1beta treatment induced a time-dependent induction of GM-CSF in HASMC. Furthermore, IL-1beta stimulated the major MAPK pathways, including ERK1/ERK2, JNK, and p38 MAPK. Exposure of HASMC to CO at low concentration (250 ppm) markedly inhibited IL-1beta-induced GM-CSF synthesis (>90%) compared with air-treated controls. CO treatment inhibited IL-1beta-induced ERK1/2 activation but did not inhibit JNK and p38 MAPK. Furthermore, CO increased cGMP levels in HASMC. Inhibition of guanylate cyclase by IH-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-1 (ODQ) abolished the inhibitory effects of CO on GM-CSF synthesis and ERK1/2 activation. Collectively, these data demonstrate that the inhibitory effect of CO on GM-CSF synthesis depends on ERK1/2 MAPK and guanylate cyclase/cGMP-dependent pathways.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 5th Avenue, Pittsburgh, PA 15213, USA.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Song
authors.forename: Wen
authors.initials: W
authors.lastname: Ning
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Bill T
authors.initials: BT
authors.lastname: Ameredes
authors.forename: William J
authors.initials: WJ
authors.lastname: Calhoun
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D002248:Carbon Monoxide / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology; D004338:Drug Combinations; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; D007375:Interleukin-1; D008070:Lipopolysaccharides; D002248:Carbon Monoxide; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP