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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-?-deficient ((-/-)) mice, in which colitis is mediated by Th2 cytokines, similar to the cytokine milieu described in human ulcerative colitis. TCR?(-/-) 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-1?, 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 TCR?(-/-) 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.

SUBMITTER: Sheikh SZ

PROVIDER: S-EPMC3172697 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis.

Sheikh Shehzad Z SZ Hegazi Refaat A RA Kobayashi Taku T Onyiah Joseph C JC Russo Steven M SM Matsuoka Katsuyoshi K Sepulveda Antonia R AR Li Fengling F Otterbein Leo E LE Plevy Scott E SE

Journal of immunology (Baltimore, Md. : 1950) 20110328 9

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 w ...[more]

PMID: 21444764

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Project description:AimsTo examine the pro-resolving effects of taurine chloramine (TauCl).ResultsTauCl injected into the peritoneum of mice enhanced the resolution of zymosan A-induced peritonitis. Furthermore, when the macrophages obtained from peritoneal exudates were treated with TauCl, their efferocytic ability was elevated. In the murine macrophage-like RAW264.7 cells exposed to TauCl, the proportion of macrophages engulfing the apoptotic neutrophils was also increased. In these macrophages treated with TauCl, expression of heme oxygenase-1 (HO-1) was elevated along with increased nuclear translocation of the nuclear factor E2-related factor 2 (Nrf2). TauCl binds directly to Kelch-like ECH association protein 1 (Keap1), which appears to retard the Keap1-driven degradation of Nrf2. This results in stabilization and enhanced nuclear translocation of Nrf2 and upregulation of HO-1 expression. TauCl, when treated to peritoneal macrophages isolated from either Nrf2 or HO-1 wild-type mice, stimulated efferocytosis (phagocytic engulfment of apoptotic neutrophils by macrophages), but not in the macrophages from Nrf2 or HO-1 knockout mice. Furthermore, transcriptional expression of some scavenger receptors recognizing the phosphatidylserines exposed on the surface of apoptotic cells was increased in RAW264.7 cells treated with TauCl. Pharmacologic inhibition of HO-1 activity or knockdown of HO-1 gene in RAW264.7 cells abolished the TauCl-induced efferocytosis, whereas both overexpression of HO-1 and treatment with carbon monoxide (CO), the product of HO, potentiated the efferocytic activity of macrophages.InnovationThis work provides the first evidence that TauCl stimulates efferocytosis by macrophages. The results of this study suggest the therapeutic potential of TauCl in the management of inflammatory disorders.ConclusionTauCl can facilitate resolution of inflammation by increasing the efferocytic activity of macrophages through Nrf2-mediated HO-1 upregulation and subsequent production of CO.

Dataset Information

An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis.

Publications

An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis.

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