title: Convergence of IL-1beta 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-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.
authors.affiliation: Division of Dermatology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America. philip@bruinphd.com
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schenk
authors.forename: Valencia P
authors.initials: VP
authors.lastname: Walker
authors.forename: Paul W
authors.initials: PW
authors.lastname: Dempsey
authors.forename: Melissa
authors.initials: M
authors.lastname: Kanchanapoomi
authors.forename: Matthew
authors.initials: M
authors.lastname: Wheelwright
authors.forename: Aria
authors.initials: A
authors.lastname: Vazirnia
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Zhang
authors.forename: Andreas
authors.initials: A
authors.lastname: Steinmeyer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zügel
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Hollis
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013234:Stem Cells; D051194:Toll-Like Receptor 1 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D023083:beta-Defensins / Q000235:genetics; D054804:Cathelicidins
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; C513975:Defb4 protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D018167:Receptors, Calcitriol; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D023083:beta-Defensins; D054804:Cathelicidins