The role of alcohol dehydrogenase 1C in regulating inflammatory responses in ulcerative colitis

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease caused by an interaction of genetics, immune responses, and environmental factors. However, the precise pathogenesis of UC remains poorly understood. The aim of the present study was to explore the potential target genes implicated in UC and to elucidate its underlying pathogenic mechanism. Firstly, three UC-associated microarray datasets (GSE75214, GSE87466, and GSE92517) were obtained to screen the differentially expressed genes (DEGs). As a result, alcohol dehydrogenase 1C (ADH1C) was the most significantly downregulated DEG in UC. We confirmed that ADH1C was downregulated in colonic tissue taken from patients with UC and colitis mice. Moreover, ADH1C expression was also decreased in colonic cell lines (NCM460 and HT29) treated with mixed proinflammatory cytokines (TNF-α, IFN-γ, IL-1β). Interestingly, we found that overexpression of ADH1C could distinctly decrease the production of IL-6 and IL-8. To elucidate the molecular mechanism of ADH1C in UC, gene set enrichment analysis (GSEA) was performed and demonstrated that immune-related pathways were mainly enriched in the low ADH1C group. Further studies displayed that STAT1/NF-κB pathway was activated in colitis mice and inflammatory cell model. Importantly, overexpression of ADH1C could suppress the phosphorylation of STAT1 and IκB. Therefore, ADH1C might regulate inflammatory responses through STAT1/NF-κB pathway. In conclusion, ADH1C was downregulated during inflammation, and its increased expression could inhibit the activation of STAT1/NF-κB pathway, thereby alleviating the secretion of IL-6 and IL-8. These findings indicate that ADH1C may be a potential therapeutic target for UC therapy.