Triggering human TLR2/1-induces distinct IL-1β- and VDR-dependent antimicrobial peptides required for host defense β (135.42)

Abstract

Abstract Activation of Toll-like receptor 2/1 (TLR2/1) on human monocytes induces a vitamin D receptor (VDR) dependent antimicrobial pathway against intracellular mycobacteria, involving the induction of the antimicrobial peptide cathelicidin. Here, we demonstrate a novel TLR-induced antimicrobial pathway leading to induction of DEFB4, requiring synergy between IL-1β- and VDR- dependent transcriptional activation. Strikingly, TLR2/1 induction of DEFB4, but not cathelicidin required IL-1β activity despite both requiring VDR activation. TLR2/1L activation triggered the upregulation of both IL-1β and IL-1 receptor, and downregulation of the IL-1 receptor antagonist. 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 activating DEFB4 but not cathelicidin. Knockdown of either DEFB4 or cathelicidin resulted in the loss of TLR2/1-mediated antimicrobial activity against intracellular mycobacterial infection in primary monocytes. Therefore, these data identify a novel mechanism of host defense requiring the induction of IL-1β in synergy with vitamin D activation, for TLR-induced antimicrobial pathway against intracellular pathogens.