title: IL-22 activates oxidant signaling in pulmonary vascular smooth muscle cells.
abstract: Reactive oxygen species (ROS) mediate cell-signaling processes in response to various ligands and play important roles in the pathogenesis of cardiovascular diseases. The present study reports that interleukin-22 (IL-22) elicits signal transduction in vascular smooth muscle cells (SMCs) through a ROS-dependent mechanism. We find that pulmonary artery SMCs express IL-22 receptor alpha 1 and that IL-22 activates STAT3 through this receptor. IL-22-induced signaling is found to be mediated by NADPH oxidase, as indicated by the observations that the inhibition and siRNA knock-down of this enzyme inhibit IL-22 signaling. IL-22 triggers the oxidative modifications of proteins through protein carbonylation and protein glutathionylation. Mass spectrometry identified some proteins that are carbonylated in response to IL-22 stimulation, including α-enolase, heat shock cognate 71kDa protein, mitochondrial 60kDa heat shock protein, and cytoplasmic 2 actin and determined that α-tubulin is glutathionylated. Protein glutathionylation and STAT3 phosphorylation are enhanced by the siRNA knock-down of glutaredoxin, while IL-22-mediated STAT3 phosphorylation is suppressed by knocking down thioredoxin interacting protein, an inhibitor of thioredoxin. IL-22 is also found to promote the growth of SMCs via NADPH oxidase. In rats, pulmonary hypertension is found to be associated with increased smooth muscle IL-22 expression. These results show that IL-22 promotes the growth of pulmonary vascular SMCs via a signaling mechanism that involves NADPH oxidase-dependent oxidation.
authors.affiliation: Department of Pharmacology and Physiology Georgetown University Medical Center Washington DC 20057 USA.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Bansal
authors.affiliation: Department of Pharmacology and Physiology Georgetown University Medical Center Washington DC 20057 USA.
authors.forename: Dividutta
authors.initials: D
authors.lastname: Das
authors.affiliation: Department of Pharmacology and Physiology Georgetown University Medical Center Washington DC 20057 USA.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Hsieh
authors.affiliation: Department of Pharmacology and Physiology Georgetown University Medical Center Washington DC 20057 USA.
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Physiology Georgetown University Medical Center Washington DC 20057 USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Gilmore
authors.affiliation: Department of Pharmacology and Physiology Georgetown University Medical Center Washington DC 20057 USA.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Department of Pharmacology and Physiology Georgetown University Medical Center Washington DC 20057 USA.
authors.forename: Yuichiro J
authors.initials: YJ
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000276:immunology; D007378:Interleukins / Q000032:analysis / Q000276:immunology*; D008168:Lung / Q000166:cytology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000276:immunology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000276:immunology*; D019255:NADPH Oxidases / Q000276:immunology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000276:immunology*; D018123:Receptors, Interleukin / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C415369:interleukin-22 receptor
keywords: Interleukin-22; Reactive oxygen species; Redox signaling; Vascular smooth muscle
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