Document Detail


CD40 ligand and interferon-γ induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes.
MedLine Citation:
PMID:  23289765     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The ability of T cells to activate antimicrobial pathways in infected macrophages is essential to host defence against many intracellular pathogens. Here, we compared the ability of two T-cell-mediated mechanisms to trigger antimicrobial responses against Mycobacterium tuberculosis in humans, CD40 activation and the release of interferon-γ (IFN-γ). Given that IFN-γ activates a vitamin D-dependent antimicrobial response, we focused on induction of the key components of this pathway. We show that activation of human monocytes via CD40 ligand (CD40L) and IFN-γ, alone, and in combination, induces the CYP27b1-hydroxylase, responsible for the conversion of 25-hydroxyvitamin D (25D) to the bioactive 1,25-dihydroxyvitamin D (1,25D), and the vitamin D receptor (VDR). The activation of the vitamin D pathway by CD40L and IFN-γ results in up-regulated expression of the antimicrobial peptides, cathelicidin and DEFB4, as well as induction of autophagy. Finally, activation of monocytes via CD40L and IFN-γ results in an antimicrobial activity against intracellular M. tuberculosis. Our data suggest that at least two parallel T-cell-mediated mechanisms, CD40L and IFN-γ, activate the vitamin D-dependent antimicrobial pathway and trigger antimicrobial activity against intracellular M. tuberculosis, thereby contributing to human host defence against intracellular infection.
Authors:
Georgiana M Klug-Micu; Steffen Stenger; Andrea Sommer; Philip T Liu; Stephan R Krutzik; Robert L Modlin; Mario Fabri
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Immunology     Volume:  139     ISSN:  1365-2567     ISO Abbreviation:  Immunology     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-09     Completed Date:  2013-06-07     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  0374672     Medline TA:  Immunology     Country:  England    
Other Details:
Languages:  eng     Pagination:  121-8     Citation Subset:  IM    
Copyright Information:
© 2013 Blackwell Publishing Ltd.
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MeSH Terms
Descriptor/Qualifier:
25-Hydroxyvitamin D3 1-alpha-Hydroxylase / immunology
Antimicrobial Cationic Peptides / immunology
CD40 Ligand / agonists,  immunology*,  metabolism
Calcitriol / immunology
Female
Humans
Interferon-gamma / agonists,  immunology*,  metabolism
Male
Monocytes / immunology*,  microbiology
Mycobacterium tuberculosis / immunology*
Receptors, Calcitriol / immunology*
T-Lymphocytes / immunology
Tuberculosis / immunology*
beta-Defensins / immunology
Grant Support
ID/Acronym/Agency:
AI047868/AI/NIAID NIH HHS; AI073539/AI/NIAID NIH HHS; AR040312/AR/NIAMS NIH HHS; P50 - AR063020/AR/NIAMS NIH HHS; R01 AI022553/AI/NIAID NIH HHS; R01 AI047868/AI/NIAID NIH HHS; R01 AR040312/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Antimicrobial Cationic Peptides; 0/DEFB4A protein, human; 0/IFNG protein, human; 0/Receptors, Calcitriol; 0/beta-Defensins; 143108-26-3/CAP18 lipopolysaccharide-binding protein; 147205-72-9/CD40 Ligand; 82115-62-6/Interferon-gamma; EC 1.14.-/25-Hydroxyvitamin D3 1-alpha-Hydroxylase; FXC9231JVH/Calcitriol
Comments/Corrections

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