Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses.

Liu, Philip T; Schenk, Mirjam; Walker, Valencia P; Dempsey, Paul W; Kanchanapoomi, Melissa; Wheelwright, Matthew; Vazirnia, Aria; Zhang, Xiaoran; Steinmeyer, Andreas; Zügel, Ulrich; Hollis, Bruce W; Cheng, Genhong; Modlin, Robert L (2009). Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. PLoS ONE, 4(6), e5810. Public Library of Science 10.1371/journal.pone.0005810

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

UniBE Contributor:

Schenk, Mirjam

ISSN:

1932-6203

Publisher:

Public Library of Science

Language:

English

Submitter:

Mirjam Schenk

Date Deposited:

25 Jul 2017 14:49

Last Modified:

25 Jul 2017 14:49

Publisher DOI:

10.1371/journal.pone.0005810

PubMed ID:

19503839

BORIS DOI:

10.7892/boris.102306

URI:

https://boris.unibe.ch/id/eprint/102306

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