期刊
ENDOCRINOLOGY
卷 158, 期 6, 页码 1951-1963出版社
ENDOCRINE SOC
DOI: 10.1210/en.2016-1913
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资金
- American Institute for Cancer Research [09A098]
- National Cancer Institute (NCI) [CA156240]
- Purdue University Center for Cancer Research, an NCI-designated basic science cancer center [P30 CA023168]
- Purdue Interdisciplinary Cancer Prevention Internship Program from the National Institutes of Health [R25 CA128770]
- Abbott Laboratories Pathology Research Fellowship
Low vitamin D status potentiates experimental colitis, but the vitamin D-responsive cell in colitis has not been defined. We hypothesized that vitamin D has distinct roles in colonic epithelial cells and in nonepithelial cells during colitis. We tested this hypothesis by using mice with vitamin D receptor (VDR) deletion from colon epithelial cells (CEC-VDRKO) or nonintestinal epithelial cells (NEC-VDRKO). Eight-week-old mice were treated with 1.35% dextran sulfate sodium (DSS) for 5 days and then euthanized 2 or 10 days after removal of DSS. DSS induced body weight loss and increased disease activity index and spleen size. This response was increased in NEC-VDRKO mice but not CECVDRKO mice. DSS-induced colon epithelial damage and immune cell infiltration scores were increased in both mouse models. Although the epithelium healed between 2 and 10 days after DSS administration in control and CEC-VDRKO mice, epithelial damage remained high in NEC-VDRKO mice 10 days after removal of DSS, indicating delayed epithelial healing. Gene expression levels for the proinflammatory, M1 macrophage (M phi) cytokines tumor necrosis factor-alpha, nitric oxide synthase 2, and interleukin-1 beta were significantly elevated in the colon of NEC-VDRKO mice at day 10. In vitro experiments in murine peritoneal M phi s demonstrated that 1,25 dihydroxyvitamin D directly inhibited M1 polarization, facilitated M2 polarization, and regulated M phi phenotype switching toward the M2 and away from the M1 phenotype. Our data revealed unique protective roles for vitamin D signaling during colitis in the colon epithelium as well as nonepithelial cells in the colon microenvironment (i.e., modulation of M phi biology).
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