Potential Role of the 15kDa Selenoprotein in Colorectal Inflammation

Previously, systemic knockout (KO) of the ER-resident 15kDa selenoprotein (Sep15, SelenoF) protected mice against the formation of chemically-induced pre-neoplastic lesions and suggested modulation of inflammatory pathways. Our objective is to elucidate the potential role of SelenoF in the early steps of colon tumorigenesis by assaying gene expression of KO mice and littermate controls (WT) that were either treated with 2% dextran sulfate sodium (DSS) to induce colitis or given water (control). Based on previous results, we hypothesize that SelenoF expression is inversely correlated with a protective interferon (IFN)-γ pro-inflammatory response. Microarray analyses of colonic mucosa suggest that knockout of SelenoF expression itself caused more significant gene expression changes than DSS treatment (inflammation). Gene pathway analyses indicated galectin-6 was the highest up-regulated gene in DSS-treated (133-fold) and untreated (30-fold) KO compared to WT mice. The top significantly changed network included genes involved in the differentiation of T-lymphocytes. Colonic gene expression changes in SelenoF-KO mice, as validated with qPCR, included up-regulation of guanylate-binding protein 1 (p=0.004), and a down-regulation of T-box transcription factor 21 (p=0.08). Interestingly, a decrease in IFN-γ levels (p=0.026) was detected in the serum of KO compared to WT mice, whereas the opposite trend was shown in colonic mucosa. Thus, our preliminary analyses indicate that SelenoF may indeed influence the expression of inflammatory genes in the colon. Its contribution to the regulation of colitis will continue to be elucidated.