The Importance of Vitamin D, the Vitamin D Receptor (VDR) and Retinoid X Receptor Alpha (RXRalpha) in Murine Colitis Development and Progression.

摘要

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 (UC) and colitis-associated cancer (CAC); however, its status in murine models of colitis has yet to be explored. To signal, VDR must heterodimerize with Retinoid X Receptor alpha (RXRalpha). If either VDR or RXRalpha are compromised, Vitamin D cannot regulate inflammatory pathways. RXRalpha is downregulated in human colorectal cancer (CRC), yet its expression in human and murine colitis has yet to be investigated. To explore the importance of Vitamin D, VDR and RXRalpha in murine colitis, we utilized acute and chronic Azoxymethane/Dextran Sulfate Sodium (AOM/DSS) models of murine colitis. VDR was found to be downregulated early in the onset of colitis whereas RXRalpha downregulation only occurred as colitis became chronic and developed into CAC. Receptor downregulation was associated with an early increase in the expression of inflammatory markers and Snail and Snail2, zinc-finger transcription factors able to transcriptionally silence VDR. 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. The acute model induced in combination with a diet supplemented with Vitamin D was unable to ameliorate colitis development or inflammatory signaling. The proof of principle experiment to demonstrate the importance of these nuclear receptors in modulating colitis development was done with an acute colitis model induced in RXRalpha+/- mice and their wild-type littermates. This experiment resulted in increased Snail and Snail2 expression in heterozygote mice. The work of this dissertation has begun to elucidate the temporality of VDR and RXRalpha downregulation in acute murine colitis and CAC as well as demonstrate the importance of Vitamin D and these nuclear receptors in modulating murine colitis development and the inflammatory signaling partially responsible for the manifestations of this disease.