Article

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

Division of Dermatology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
PLoS ONE (Impact Factor: 3.53). 02/2009; 4(6):e5810. DOI: 10.1371/journal.pone.0005810
Source: PubMed

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-1beta and vitamin D receptor (VDR) pathways. TLR2/1 activation triggered IL-1beta activity, involving the upregulation of both IL-1beta and IL-1 receptor, and downregulation of the IL-1 receptor antagonist. TLR2/1L induction of IL-1beta 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-kappaB sites, whereas the cathelicidin promoter had three VDREs and no NF-kappaB sites. Transfection of NF-kappaB 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-1beta in synergy with vitamin D activation, for the TLR-induced antimicrobial pathway against an intracellular pathogen.

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    • "Triggering of TLR2/1 was found to modulate IL-1β activity and increase the cell's responsiveness to IL-1β by simultaneously (i) inducing IL-1β secretion, (ii) increasing expression of cell surface IL-1 receptor 1 (IL- 1R1), and (iii) decreasing the baseline secretion of IL-1 receptor antagonist (IL-1RA; Liu et al., 2009). Loss of CAMP or DEFB4 expression, as well as blockage of the vitamin D pathway, ablated the TLR2/1-induced antimicrobial activity, implicating the vitamin D antimicrobial pathway as a critical part of the innate immune response against M. tuberculosis (Liu et al., 2006, 2009). Interestingly, although TLR2/1 activation of monocytes induces antimicrobial activity against M. tuberculosis infection (Thoma-Uszynski et al., 2001; Liu et al., 2006, 2012), it was insufficient to trigger antimicrobial activity against M. leprae infection (Liu et al., 2012). "
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    • "Thus, activation of macrophage Toll-like receptors (TLRs) by intracellular bacteria such as Mycobacterium tuberculosis upregulates VDR and CYP27B1 genes that allow the induction of the antimicrobial peptide cathelicidin by 1α,25(OH) 2 D 3 (Liu et al., 2006). In monocytes, TLR activation triggers induction of defensin β4 (DEFB4) gene requiring the cooperation between IL-1β and 1α,25(OH) 2 D 3 , which is explained by the presence of one VDRE and two IL-1β-activatable NFkB sites in the DEFB4 promoter (Liu et al., 2009). In addition, 1α,25(OH) 2 D 3 is required for the antimicrobial effect of IFN-γ in human macrophages (Fabri et al., 2011). "
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    • "Interestingly, nuclear receptors are known to regulate the expressions of defensins [122] [127]. Nuclear receptors represent a class of intracellular transcription factors activated by ligands which can directly interact with DNA; as a result, nuclear receptors play significant roles in the regulation of metabolic, reproductive, developmental, and immune processes [128] [129] [130] [131]. "
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