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-3β in mice model. To support the in vivo observation, TNF-α, iNOS and IL-10 after CO and LiCl treatment were measured in mesenteric lymph node cells (MLNs) and bone marrow-derived macrophages (BMMs) from DSS treated mice. In addition, we determined that CO potentially inhibited GSK-3β activation and decreased TNF-α and iNOS expression by inhibition of NF-κB activation in LPS-stimulated U937 and MLN cells pretreated with CO. Together, our findings indicate that CO attenuates DSS-induced colitis via inhibition of GSK-3β 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-3β in DSS-induced colitis model. 1. Introduction Inflammatory bowel diseases (IBD) are a chronic and recurrent intestinal inflammation resulting from the transmural infiltration of neutrophils, macrophages, lymphocytes, and mast cells, ultimately giving rise to mucosal disruption and ulceration [1]. Furthermore, defects in epithelial barrier function and overproduction of proinflammatory cytokines such as IL-1β, IL-6, IL-12p40, IL-23p19, TNF-α and IFN-γ lead to tissue injury in intestine [2]. Additionally, upregulation of pro-inflammatory cytokines in IBD condition is mediated by NF-κB, a transcription factor [3]. In order to develop the various models of experimental IBD, dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) was administrated [4, 5]. This model is characterized by acute tissue inflammation in the colon and mimics the pathology of human ulcerative colitis. Endogenous carbon monoxide (CO) as the end product of heme oxygenase-1 (HO-1) activity has anti-inflammatory, antiapoptotic and cytoprotective properties [6]. Also, CO ameliorates active inflammation in an experimental model of chronic IBD [7, 8]. Further, CO has showen beneficial effects in ischemia/reperfusion injury [9, 10], pulmonary inflammation [11], and sepsis [12]. In case of tracheal transplantation in
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