Immunomodulating effect of vitamin D3 derivatives on type-1 cellular immunity

Abstract

ABSTRACT1α,25-dihydroxyvitamin D3 [Calcitriol or 1,25(OH) 2 D 3 ] is an important active metabolite involved in multiple functions but its calcemic effect in vivo limits its therapeutic applications. On the other hand, 22-oxa-1α,25-dihydroxyvitamin D 3 (22-oxacalcitriol or 22-Oxa-1α,25-D 3 ), a low calcemic analog of vitamin D3 (VitD3), has been widely used as a drug for the secondary hyperparathyroidism. Here, we investigated immunomodulating effect of these two VitD3 derivatives on the differentiation of type-1 immunoregulatory cells such as dendritic cells (DC1), cytotoxic T cells (Tc1) and helper T cells (Th1). BALB/c mouse bone marrow-derived DC (BMDC1) induced by culture with Th1 condition (GM-CSF, IL-3, IL-12 and IFN-γ) expressed higher levels of MHC Class I and Class II molecules and co-stimulatory molecules compared with BMDC0 induced by neutral condition (GM-CSF + IL-3). In addition, BMDC1 showed stronger immunostimulating activity to induce alloantigen (H-2 d )-specific cytotoxic T lymphocytes (CTL) compared with BMDC0. However, if VitD3 derivatives were added into the culture for BMDC1 induction, the expression of functional molecules and type-1 IFNs were greatly inhibited. Moreover, VitD3 derivative-treated BMDC1 lost their immunostimulating activity to induce alloantigen-specific IFN-γ-producing Tc1. In addition, it was demonstrated that the addition of VitD3 derivatives inhibited the differentiation of IFN-γ-producing Th1 cells from ovalbumin (OVA)-specific naive Th cells, while it rather augmented the differentiation of IL-4-or IL-10-producing Th2 cells. There was no significant difference in immunomodulating activity between 1,25(OH) 2 D 3 and 22-Oxa-1α,25-D 3 . Thus, VitD3 derivatives are demonstrated to inhibit the functional differentiation of DC1, Tc1 and Th1 cells, which play a critical role in type-1 cellular immune responses.

1,25-dihydroxyvitamin D3 Modulates Cytokine Production Induced by Candida albicans: Impact of Seasonal Variation of Immune Responses

“…We have shown that 1,25(OH) 2 D 3 has a distinct propensity to skew host response to C. albicans away from a ''proinflammatory'' profile through attenuation of TNF-a, IL-6, IFN-c as well as production of IL-17. Other researchers have reported inhibition of Th1 cytokine production with 1,25(OH) 2 D 3 , although not in the setting of Candida infection and polarization toward a Th2-type response [21][22][23]. In our system using human PBMC stimulated by C. albicans, we also observed an increase in IL-10 production in vitamin D presence.…”

Feeding the immune system

“…Its effects include promotion of phagocytosis, superoxide synthesis and bacterial killing, but it is also reported to inhibit T-cell proliferation and production of Th1-type cytokines (74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84) and of antibodies by B-cells (85) , highlighting the paradoxical nature of its effects. Effects on Th2-type responses are not clear (86)(87)(88) and there may be an increase in numbers of regulatory T-cells (89,90) . Overall, the current evidence suggests that vitamin D is a regulator of immune function but that its effects will depend upon the immunological situation (e.g.…”

1,25-Dihydroxyvitamin D3 inhibits proliferation but not the suppressive function of regulatory T cells in the absence of antigen-presenting cells

“…With regard to conventional T cells, it has been shown that 1,25(OH) 2 D 3 and its analogues have the capacity to inhibit T-cell proliferation [32][33][34] and to modulate cytokine production 35,36 when activated with mitogens. Secretion of interferon-c and IL-17 was inhibited, 23 and IL-4 and IL-10 production was enhanced 23,[37][38][39] thereby favouring a bias towards Th2 differentiation.…”