Convergence of IL-1β and VDR Activation Pathways in Human TLR2/1-Induced Antimicrobial Responses

Abstract

Antimicrobial effector mechanisms are central to the function of the innate immune response in host defense against microbial pathogens. In humans, activation of Toll-like receptor 2/1 (TLR2/1) on monocytes induces a vitamin D dependent antimicrobial activity against intracellular mycobacteria. Here, we report that TLR activation of monocytes triggers induction of the defensin beta 4 gene (DEFB4), requiring convergence of the IL-1β and vitamin D receptor (VDR) pathways. TLR2/1 activation triggered IL-1β activity, involving the upregulation of both IL-1β and IL-1 receptor, and downregulation of the IL-1 receptor antagonist. TLR2/1L induction of IL-1β was required for upregulation of DEFB4, but not cathelicidin, whereas VDR activation was required for expression of both antimicrobial genes. The differential requirements for induction of DEFB4 and cathelicidin were reflected by differences in their respective promoter regions; the DEFB4 promoter had one vitamin D response element (VDRE) and two NF-κB sites, whereas the cathelicidin promoter had three VDREs and no NF-κB sites. Transfection of NF-κB into primary monocytes synergized with 1,25D3 in the induction of DEFB4 expression. Knockdown of either DEFB4 or cathelicidin in primary monocytes resulted in the loss of TLR2/1-mediated antimicrobial activity against intracellular mycobacteria. Therefore, these data identify a novel mechanism of host defense requiring the induction of IL-1β in synergy with vitamin D activation, for the TLR-induced antimicrobial pathway against an intracellular pathogen.

Immunological role of vitamin D at the maternal–fetal interface

“…Although, to date, this possibility has not been addressed in purified decidual monocytes/macrophages, studies using unpurified first-trimester decidual cells have shown 25OHD-and 1,25(OH) 2 D-mediated induction of cathelicidin (Evans et al 2006). It is also important to recognise that intracrine activation of vitamin D promotes antibacterial responses beyond simple induction of cathelicidin and other antibacterial proteins such as b-defensins (Liu et al 2009). These include the induction of autophagy (Shin et al 2011) and possible effects on intracellular iron concentrations via the iron export modulator hepcidin (Bacchetta et al 2014).…”

Hypoxia Triggers the Expression of Human β Defensin 2 and Antimicrobial Activity against Mycobacterium tuberculosis in Human Macrophages

“…We recently identified an antimicrobial pathway that is triggered by VDR and results in the cathelicidin and hBD2-mediated killing of M. tuberculosis (16)(17)(18). To evaluate whether this cascade is affected by the restriction of oxygen supply, we cultured M. tuberculosis-infected MDM at 20 or 1% oxygen overnight and measured the expression of VDR by quantitative LightCycler PCR.…”

The effect of vitamin D on women’s reproductive health

“…Врожденный иммунитет активируется неза-медлительно, при первом же контакте с ми-кробным антигеном. Этот процесс может стимулировать витамин D, миелоидные и эпи-телиальные клетки, которые экспрессируют Toll-like-рецепторы (TLR) [32][33][34], cYP27B1 и VDR. У людей существуют десять видов TLR, которые активируются посредством их связи с лигандами антигенов микробного происхож-дения.…”