Abstract
Both autophagy and pro-inflammatory cytokines are involved in the host defence against mycobacteria, but little is known regarding the effect of autophagy on Mycobacterium tuberculosis (MTB)-induced cytokine production. In the present study, we assessed the effect of autophagy on production of monocyte-derived and T-cell-derived cytokines, and examined whether two functional polymorphisms in autophagy genes led to altered cytokine production. Blocking autophagy inhibited tumour necrosis factor-α (TNF-α) production, while enhancing interleukin-1β (IL-1β) production in peripheral blood mononuclear cells stimulated with MTB. Induction of autophagy by starvation or interferon-γ (IFN-γ) had the opposite effect. The modulation of both TNF-α and IL-1β production by autophagy was induced at the level of gene transcription. Functional polymorphisms in the autophagy genes ATG16L1 and IRGM did not have a major impact on MTB-induced cytokine production in healthy volunteers, although a moderate effect was observed on IFN-γ production by the ATG16L1 T300A polymorphism. These data demonstrate the interplay between autophagy and inflammation during host defence against mycobacteria, and future studies to investigate the clinical implications of these effects for the susceptibility to tuberculosis are warranted.
© 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Autophagy / genetics
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Autophagy / immunology*
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Autophagy-Related Protein 7
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Autophagy-Related Proteins
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Cells, Cultured
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Cytokines / genetics
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Cytokines / immunology*
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Cytokines / metabolism
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Enzyme-Linked Immunosorbent Assay
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / immunology
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Host-Pathogen Interactions / immunology
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Humans
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism
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Leukocytes, Mononuclear / immunology*
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Leukocytes, Mononuclear / metabolism
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Leukocytes, Mononuclear / microbiology
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Mycobacterium tuberculosis / immunology*
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Mycobacterium tuberculosis / physiology
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Polymorphism, Single Nucleotide / immunology
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription, Genetic / immunology
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
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Ubiquitin-Activating Enzymes / genetics
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Ubiquitin-Activating Enzymes / immunology
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Ubiquitin-Activating Enzymes / metabolism
Substances
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ATG16L1 protein, human
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Autophagy-Related Proteins
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Carrier Proteins
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Cytokines
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Interleukin-1beta
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Tumor Necrosis Factor-alpha
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GTP-Binding Proteins
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IRGM protein, human
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ATG7 protein, human
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Autophagy-Related Protein 7
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Ubiquitin-Activating Enzymes