Vitamin D Receptor and Retinoid X Receptor α Status and Vitamin D Insufficiency in Models of Murine Colitis

Abstract

The anti-inflammatory actions of vitamin D have long been recognized and its importance in modulating colon cancer and colitis development is becoming apparent. The vitamin D receptor (VDR) is downregulated in human ulcerative colitis and colitis-associated cancer (CAC); however, its status in murine models of colitis has yet to be explored. Snail and Snail2, zinc-finger transcription factors regulated by inflammatory pathways and able to transcriptionally silence VDR, are upregulated in human Ulcerative Colitis and are associated with localized VDR silencing. To signal, VDR must heterodimerize with retinoid X receptor α (RXRα). If either VDR or RXRα are compromised, vitamin D cannot regulate inflammatory pathways. RXRα is downregulated in human colorectal cancer, yet its expression in human and murine colitis has yet to be investigated. To explore the importance of vitamin D and VDR in murine colitis, we used acute and chronic azoxymethane/dextran sulfate sodium models of murine colitis. VDR was downregulated early in the onset of colitis, whereas RXRα downregulation only occurred as colitis became chronic and developed into CAC. Receptor downregulation was associated with an early increase in the expression of the inflammatory markers, Snail and Snail2. The acute colitis model induced in combination with a vitamin D-deficient diet resulted in increased morbidity, receptor downregulation, inflammatory marker expression, and Snail and Snail2 upregulation. These experiments show the importance of vitamin D and VDR in modulating murine colitis development.