Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D

Abstract

Non-classical actions of vitamin D were first suggested over 30 years ago when receptors for the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), were detected in various tissues and cells that are not associated with the regulation of calcium homeostasis, including activated human inflammatory cells. The question that remained was the biological significance of the presence of vitamin D receptors in the different tissues and cells and, with regard to the immune system, whether or not vitamin D plays a role in the normal immune response and in modifying immune mediated diseases. In this article findings indicating that vitamin D is a key factor regulating both innate and adaptive immunity are reviewed with a focus on the molecular mechanisms involved. In addition, the physiological significance of vitamin D action, as suggested by in vivo studies in mouse models is discussed. Together, the findings indicate the importance of 1,25(OH)2D3 as a regulator of key components of the immune system. An understanding of the mechanisms involved will lead to potential therapeutic applications for the treatment of immune mediated diseases.

Keywords: autoimmune disease; cathelicidin; vitamin D.

Figure 1

1,25(OH)₂D₃ is a key transcriptional regulator of components of the immune system. Summary of transcriptional mechanisms by which 1,25(OH)₂D₃ modulates both innate and adaptive immunity.

Figure 2

Transgenic mice (Knockout/transgenic 2 (KO/TG2)) expressing vitamin D receptor (VDR) exclusively in the distal intestine at levels equivalent to wild type (WT) are less sensitive to colitis induced by dextran sulfate sodium (DSS) than VDR KO mice. Symptoms of colitis are more severe in the KO/TG3 line which expresses low levels of VDR exclusively in the distal intestine. Colonic bleeding is attenuated in in both KO/TG2 and KO/TG3 mice by 1,25(OH)₂D₃ treatment. (A) Left panel: Real time-PCR (RT-PCR) hVDR mRNA: VDR KO mice expressing hVDR specifically in ileum, cecum, and colon were generated (results shown are for KO/TG2: for all three KO/TG lines VDR mRNA was only observed in ileum, cecum and colon); Right panel: Representative Western blot of VDR using 50 µg of nuclear protein (D, duodenum; J, jejunum; I, Ileum; Ce, cecum; C, colon). Ponceau S staining was used as the loading control. (B) Rectal bleeding score following DSS administration. Mice consumed 3% DSS ad libitum in the drinking water for six days and resumed water alone for one day before killing. Rectal bleeding was assessed on a scale from 0 to 4. Since male and female mice responded similarly to DSS, both genders were used in the DSS colitis experiments. (C) Representative H & E stained colon sections from mice killed on day seven post initiation of DSS treatment. Severe crypt disruption and infiltration of immune cells are observed in VDR KO and KO/TG3 mice. (D) Colonic length of mice killed seven days post initiation of the DSS treatment; (E) Colonic blood score (0, no blood detected to 3, blood visible throughout the colon) of mice killed on day seven post initiation of DSS treatment. No blood was detected (N.D.) in WT or KO/TG2 mice treated with 1,25(OH)₂D₃ (0.5 ng/g bw, ip) one day prior to DSS administration and every other day thereafter. 1,25(OH)₂D₃ treatment of KO/TG3 mice resulted in an attenuated blood score. Veh; vehicle (propylene glycol). * p < 0.05 compared to WT and KO/TG2. + p < 0.05 compared to vehicle treated KO/TG3 mice. Values are means ± SEMs, n = 3–4 per group. (F) Representative RT-PCR analysis of E-cadherin mRNA expression in colon of DSS treated WT, KO/TG2 and KO/TG3 mice receiving vehicle (Veh) or 1,25(OH)₂D₃. RT-PCR is representative of 3 separate experiments for WT and KO/TG2 mice and two separate experiments for KO/TG3 mice. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Rutgers, New Jersey Medical School.