An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis
Journal of Immunology
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 TCRβ-/- 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. Copyright © 2011 by The American Association of Immunologists, Inc.
Sheikh, S., Hegazi, R., Kobayashi, T., Onyiah, J., Russo, S., Matsuoka, K., Sepulveda, A., Li, F., Otterbein, L., & Plevy, S. (2011). An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis. Journal of Immunology, 186 (9). http://dx.doi.org/10.4049/jimmunol.1002433