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PATHOGENESIS

Liu W, Chen Y, Golan MA et al. J Clin Invest 2013;123:3983–96.

This study demonstrates the importance of epithelial vitamin D receptor (VDR) signaling in inhibiting colitis via protection of the mucosal epithelial barrier. This effect is independent of VDR-mediated actions in the non-epithelial immune system.

 

The biological activity of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) is mediated by the vitamin D receptor (VDR), a member of the nuclear hormone receptor superfamily. Epidemiological data demonstrate an association between vitamin D deficiency and an increased risk of IBD. A high prevalence of vitamin D deficiency is reported in patients with established as well as newly diagnosed IBD. VDR gene polymorphisms have also been reported to be associated with IBD. These observations suggest that vitamin D status might be an environmental determinant for IBD, whereas VDR status may be a genetic factor influencing IBD development. In this study, VDR, which is typically highly expressed in intestinal epithelial cells (IEC), was shown to be reduced in ulcerative colitis and Crohn’s disease. The relative levels of VDR protein were also decreased in active versus uninflamed mucosal sections in IBD. The authors found no relationship between serum vitamin D levels and IBD disease status. Using a transgenic mouse model overexpressing the human VDR in the gut, the authors demonstrated a protective effect against trinitrobenzene sulfate-, dextran sodium sulfate-, and T-cell transfer-induced colitis. Reconstitution of VDR-deficient IECs with the human VDR transgene completely rescued VDR-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive VDR-deficient immune system. Mechanistically, VDR signaling attenuated p53-upregulated modulator of apoptosis (PUMA) induction in IECs by blocking nuclear factor-κB activation, leading to a reduction in IEC apoptosis.

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