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

被引:249
作者
Liu, Philip T.
Schenk, Mirjam
Walker, Valencia P.
Dempsey, Paul W.
Kanchanapoomi, Melissa
Wheelwright, Matthew
Vazirnia, Aria
Zhang, Xiaoran
Steinmeyer, Andreas
Zuegel, Ulrich
Hollis, Bruce W.
Cheng, Genhong
Modlin, Robert L.
机构
[1] Division of Dermatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA
[2] Neonatal Research Center, Division of Neonatology and Developmental Biology, University of Los Angeles, Los Angeles, CA
[3] Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA
[4] School of Medicine, University of California San Francisco, San Francisco, CA
[5] Department of Medicinal Chemistry, Bayer Schering Pharma AG, Berlin
[6] Common Mechanism Research Early Projects, Bayer Schering Pharma AG, Berlin
[7] Department of Pediatrics, Medical University of South Carolina, Charleston, SC
来源
PLOS ONE | 2009年 / 4卷 / 06期
关键词
D O I
10.1371/journal.pone.0005810
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-1 beta and vitamin D receptor (VDR) pathways. TLR2/1 activation triggered IL-1 beta activity, involving the upregulation of both IL-1 beta and IL-1 receptor, and downregulation of the IL-1 receptor antagonist. TLR2/1L induction of IL-1 beta 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-kappa B sites, whereas the cathelicidin promoter had three VDREs and no NF-kappa B sites. Transfection of NF-kappa B 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-1 beta in synergy with vitamin D activation, for the TLR-induced antimicrobial pathway against an intracellular pathogen.
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页数:13
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