Carbon Monoxide Attenuates Dextran Sulfate Sodium-Induced Colitis via Inhibition of GSK-3 beta Signaling

Abstract

Endogenous carbon monoxide (CO) is produced by heme oxygenase-1 (HO)-1 which mediates the degradation of heme into CO, iron, and biliverdin. Also, CO ameliorates the human inflammatory bowel diseases and ulcerative colitis. However, the mechanism for the effect of CO on the inflammatory bowel disease has not yet been known. In this study, we showed that CO significantly increases survival percentage, body weight, colon length as well as histologic parameters in DSS-treated mice. In addition, CO inhalation significantly decreased DSS induced pro-inflammatory cytokines by inhibition of GSK-3 beta in mice model. To support the in vivo observation, TNF-beta, iNOS and IL-10 afterCOand LiCl treatmentweremeasured inmesenteric lymph node cells (MLNs) and bonemarrow-derivedmacrophages (BMMs) fromDSS treated mice. In addition, we determined that CO potentially inhibited GSK-3.. activation and decreased TNF-alpha and iNOS expression by inhibition of NF-kappa B activation inLPS-stimulatedU937 andMLN cells pretreated with CO. Together, our findings indicate that CO attenuates DSS-induced colitis via inhibition of GSK-3 beta signaling in vitro and in vivo. Importantly, this is the first report that investigated the molecular mechanisms mediated the novel effects of CO via inhibition GSK-3 beta in DSS-induced colitis model.