title: An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis.
abstract: Cigarette smoking is a significant environmental factor in the human inflammatory bowel diseases, remarkably, conferring protection in ulcerative colitis. We previously demonstrated that a prominent component of cigarette smoke, CO, suppresses Th17-mediated experimental colitis in IL-10(-/-) mice through a heme oxygenase (HO)-1-dependent pathway. In this study, homeostatic and therapeutic effects of CO and HO-1 were determined in chronic colonic inflammation in TCR-α-deficient ((-/-)) mice, in which colitis is mediated by Th2 cytokines, similar to the cytokine milieu described in human ulcerative colitis. TCRα(-/-) mice exposed to CO or treated with the pharmacologic HO-1 inducer cobalt protoporphyrin demonstrated amelioration of active colitis. CO and cobalt protoporphyrin suppressed colonic IL-1β, TNF, and IL-4 production, whereas IL-10 protein secretion was increased. CO induced IL-10 expression in macrophages and in vivo through an HO-1-dependent pathway. Bacterial products regulate HO-1 expression in macrophages through MyD88- and IL-10-dependent pathways. CO exposure and pharmacologic HO-1 induction in vivo resulted in increased expression of HO-1 and IL-10 in CD11b(+) lamina propria mononuclear cells. Moreover, induction of the IL-10 family member IL-22 was demonstrated in CD11b(-) lamina propria mononuclear cells. In conclusion, CO and HO-1 induction ameliorated active colitis in TCRα(-/-) mice, and therapeutic effects correlated with induction of IL-10. This study provides further evidence that HO-1 mediates an important homeostatic pathway with pleiotropic anti-inflammatory effects in different experimental models of colitis and that targeting HO-1, therefore, is a potential therapeutic strategy in human inflammatory bowel diseases.
authors: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors: Shehzad Z
authors: SZ
authors: Sheikh
authors: Refaat A
authors: RA
authors: Hegazi
authors: Taku
authors: T
authors: Kobayashi
authors: Joseph C
authors: JC
authors: Onyiah
authors: Steven M
authors: SM
authors: Russo
authors: Katsuyoshi
authors: K
authors: Matsuoka
authors: Antonia R
authors: AR
authors: Sepulveda
authors: Fengling
authors: F
authors: Li
authors: Leo E
authors: LE
authors: Otterbein
authors: Scott E
authors: SE
authors: Plevy
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000494:pharmacology*; D002469:Cell Separation; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051547:Heme Oxygenase-1 / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D016753:Interleukin-10; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1