Inhibition of epithelial SHH signaling exerts a dual protective effect against inflammation and epithelial-mesenchymal transition in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a debilitating and incurable inflammatory disorder. Despite its increasing prevalence, the underlying pathogenic mechanisms of IBD have not been fully clarified. In addition to the regulatory role of Sonic Hedgehog (SHH) signaling in the maintenance of gut homeostasis, its involvement in development of inflammatory disorders and organ fibrosis has also been reported. Here, we investigated the role of SHH signaling in IBD and examined the molecular mechanisms targeted by the SHH signaling blockade. In addition to increased inflammatory responses and induced Epithelial-mesenchymal transition (EMT) process, SHH signaling activity also increased in active lesions of IBD patients. These findings were similar to what was observed in the LPS-induced Caco2-RAW264.7 co-culture model. Inhibition of SHH signaling in the intestinal epithelial cells using SHH inhibitors influenced inflammatory responses through decreased expression of inflammatory cytokines. Moreover, treatment of differentiated Caco2 cells with SHH signaling inhibitors prevented the overexpression of EMT markers and downregulation of epithelial adherens and tight junctions in inflammatory conditions. This study demonstrated that the inhibition of SHH signaling by small molecules might have therapeutic benefit in IBD, and provided compelling experimental evidence that SHH signaling inhibitors can impose anti-inflammatory effects in intestinal epithelial cells while preserving their epithelial characteristics by restricting the induction of EMT.