[30] In addition to inducing CD14 for innate immunity, 1,25-dihydroxyvitamin D can

also up-regulate antimicrobial peptides such as cathelicidin and beta-defensin by macrophages in the gastrointestinal track.[13, 31] In fact, activation of toll-like receptors in human macrophages can induce cathelicidin antimicrobial peptide, which is inhibited by either a VDR antagonist or Lorlatinib a non-specific inhibitor against 1-hydroxylase activity, suggesting that de novo synthesis of 1,25-dihydroxyvitamin D is required for cathelicidin induction.[32] Induction of beta-defensin expression by 1,25-dihydroxylvitamin D requires additional activation of NF-kappaB sites, which are adjacent to its VDRE via a mechanism involving IL-1, suggesting converge of inflammatory signals and immune regulation.[33] Thus, VD-induced antimicrobial

peptides in the gastrointestinal track may represent a typical example of host defense modulation of the innate immune system. Th1 cells secrete pro-inflammatory cytokines, including interferon-gamma (IFN-gamma) and IL-2, and activate B cells to produce immunoglobulin IgG2a. A large body of evidence has demonstrated that VD/VDR can suppress Th1 lymphocytes by mechanisms such as down-regulation of IL-2, a key cytokine for T cell proliferation and activation.[34] BMS-777607 clinical trial Moreover, 1,25-dihydroxyvitamin D also suppresses IL-12 and IFN-gamma, the two major Th1 cytokines for acute immune responses.[35] In contrast, Th2 cells secrete IL-4 and IL-10, and induce the production of IgG1 and immunoglobulin E (IgE) by B cells, in a manner skewed to immune regulation. Interestingly, activated monocytes and dendritic cells from the innate immune system, and B cells from the find more adaptive immune system produce IL-12, which induces Th0 to become Th1 cells. Consequently, activated Th1 cells induce inflammation by generating IFN-gamma and TNF-alpha. For such regards, 1,25-dihydroxyvitamin D suppresses IL-12 production by

monocytes and B cells, thus consequently restraining Th1 activation.[36] Epidemiologic studies have shown that low blood VD levels are associated with autoimmune diseases. In particular, the potential role of VD in immune regulation by induction of T-regulatory cells (Tregs) is under extensive scrutiny. For example, bioactive VD was found to potentiate Treg activity,[37] and low levels of 25-hydroxy VD in the circulation are associated with compromised Treg function and high incidence of multiple sclerosis.[38] Accordingly, one study showed that high levels of 1,25-dihydroxyvitamin D are relevant to Th2 skew and increased Tregs in multiple sclerosis.[39] In a skin immune lesion model, topical application of 1,25-dihydroxlvitamin D can suppress antigen-induced CD8+ cell activation through induction of antigen-specific Tregs.