Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses.
Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses.
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DOI：
10.1371/journal.pone.0005810
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发表时间：
2009-06-05
期刊：
影响因子：
3.7
通讯作者：
Modlin RL
中科院分区：
文献类型：
--
作者：
Liu PT;Schenk M;Walker VP;Dempsey PW;Kanchanapoomi M;Wheelwright M;Vazirnia A;Zhang X;Steinmeyer A;Zügel U;Hollis BW;Cheng G;Modlin RL
抗菌效应机制是宿主防御微生物病原体的先天免疫反应功能的核心。在人类中，单核细胞上toll样受体2/1 （TLR2/1）的激活可诱导维生素D依赖性的抗细胞内分枝杆菌的抗菌活性。在这里，我们报道了TLR激活单核细胞触发防御素β 4基因（DEFB4）的诱导，需要IL-1β和维生素D受体（VDR）途径的收敛。TLR2/1激活触发IL-1β活性，涉及IL-1β和IL-1受体的上调，IL-1受体拮抗剂的下调。DEFB4的上调需要TLR2/1L诱导IL-1β，但不需要cathelicidin，而两个抗菌基因的表达都需要VDR激活。DEFB4和cathelicidin对诱导的不同要求反映在它们各自启动子区域的差异上；DEFB4启动子具有1个维生素D应答元件（VDRE）和2个NF-κB位点，而cathelicidin启动子具有3个VDRE位点和无NF-κB位点。NF-κB转染原代单核细胞与1,25 d3协同诱导DEFB4表达。原代单核细胞中DEFB4或cathelicidin的敲低都会导致tlr2 /1介导的对细胞内分枝杆菌的抗菌活性丧失。因此，这些数据确定了一种新的宿主防御机制，需要诱导IL-1β与维生素D激活协同作用，用于tlr诱导的抗细胞内病原体的抗菌途径。
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.
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DOI：
10.1084/jem.175.4.1111
发表时间：
1992-04-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chan J;Xing Y;Magliozzo RS;Bloom BR
通讯作者：
Bloom BR
影响因子：
32.4
作者：
Miller, LS;O'Connell, RM;Modlin, RL
通讯作者：
Modlin, RL
影响因子：
5.4
作者：
ANDERSSON, J;BJORK, L;ANDERSSON, U
通讯作者：
ANDERSSON, U
影响因子：
4.4
作者：
Liu, PT;Krutzik, SR;Modlin, RL
通讯作者：
Modlin, RL
影响因子：
4.8
作者：
Gombart, AF;Borregaard, N;Koeffler, HP
通讯作者：
Koeffler, HP