Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses.
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-06-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2686169?pdf=render |
| _version_ | 1818481442503524352 |
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| author | Philip T Liu Mirjam Schenk Valencia P Walker Paul W Dempsey Melissa Kanchanapoomi Matthew Wheelwright Aria Vazirnia Xiaoran Zhang Andreas Steinmeyer Ulrich Zügel Bruce W Hollis Genhong Cheng Robert L Modlin |
| author_facet | Philip T Liu Mirjam Schenk Valencia P Walker Paul W Dempsey Melissa Kanchanapoomi Matthew Wheelwright Aria Vazirnia Xiaoran Zhang Andreas Steinmeyer Ulrich Zügel Bruce W Hollis Genhong Cheng Robert L Modlin |
| author_sort | Philip T Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T11:35:07Z |
| format | Article |
| id | doaj.art-d2709e7c21bd4bed8b82ec2be53446fd |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T11:35:07Z |
| publishDate | 2009-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-d2709e7c21bd4bed8b82ec2be53446fd2022-12-22T01:50:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-06-0146e581010.1371/journal.pone.0005810Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses.Philip T LiuMirjam SchenkValencia P WalkerPaul W DempseyMelissa KanchanapoomiMatthew WheelwrightAria VazirniaXiaoran ZhangAndreas SteinmeyerUlrich ZügelBruce W HollisGenhong ChengRobert L ModlinAntimicrobial 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.http://europepmc.org/articles/PMC2686169?pdf=render |
| spellingShingle | Philip T Liu Mirjam Schenk Valencia P Walker Paul W Dempsey Melissa Kanchanapoomi Matthew Wheelwright Aria Vazirnia Xiaoran Zhang Andreas Steinmeyer Ulrich Zügel Bruce W Hollis Genhong Cheng Robert L Modlin Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. PLoS ONE |
| title | Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. |
| title_full | Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. |
| title_fullStr | Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. |
| title_full_unstemmed | Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. |
| title_short | Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. |
| title_sort | convergence of il 1beta and vdr activation pathways in human tlr2 1 induced antimicrobial responses |
| url | http://europepmc.org/articles/PMC2686169?pdf=render |
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