Interleukin-17A differentially modulates BCG induction of cytokine production in human blood macrophages

IL‐17A up‐regulates BCG‐induced IL‐6 expression via activation of the ERK1/2 pathway and enhancement of IL‐6 mRNA stability. The pathogenesis of Mtb depends in part on cytokine cross‐regulation between macrophages and T cells in host immunity. Th17 cells produce IL‐17A to induce granuloma formation...

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Bibliographic Details
Published in:Journal of leukocyte biology 2011-08, Vol.90 (2), p.333-341
Main Authors: Fang, J. W., Li, James C. B., Au, K. Y., Yim, Howard C. H., Lau, Allan S. Y.
Format: Article
Language:English
Subjects:
Cytokines - biosynthesis
helper T cells
Humans
Immunity, Innate
inflammation
Interleukin-17 - immunology
Macrophages - metabolism
Macrophages - virology
Mycobacterium
Mycobacterium bovis - immunology
Mycobacterium Infections - immunology
Transcriptional Activation - immunology
tuberculosis
Tumor Necrosis Factor-alpha - pharmacology
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Summary:IL‐17A up‐regulates BCG‐induced IL‐6 expression via activation of the ERK1/2 pathway and enhancement of IL‐6 mRNA stability. The pathogenesis of Mtb depends in part on cytokine cross‐regulation between macrophages and T cells in host immunity. Th17 cells produce IL‐17A to induce granuloma formation and to restrict mycobacterial dissemination. IL‐17A also mediates cytokine responses induced by proinflammatory cytokines such as TNF‐α. Our previous results showed that BCG induces IL‐6, IL‐10, and TNF‐α via activity of protein kinases, including dsRNA‐activated serine/threonine protein kinase and glycogen synthase kinase‐3 in primary human monocytes. Therefore, we investigated whether IL‐17A, upon its induction by BCG, plays an additional role to aid the production of downstream proinflammatory cytokines in macrophages. Here, we showed that IL‐17A enhanced IL‐6 mRNA and protein levels inducible by BCG in a time‐ and dose‐dependent manner, whereas it had no effect on IL‐10 and TNF‐α production. We also demonstrated that IL‐17A activated the phosphorylation of ERK1/2 triggered by BCG. With the use of a specific chemical inhibitor of a MAPK/ERK‐activating kinase (MEK1/2), we confirmed the correlation between the enhanced ERK1/2 activation and augmented IL‐6 production. Additionally, we revealed that IL‐17A acts in concert with BCG‐induced TNF‐α to enhance the level of IL‐6 synthesis. Taken together, our results suggest a significant role of IL‐17A to serve as a modulator of cytokine expression in innate immune response during mycobacterial infection.
ISSN:0741-5400
1938-3673
DOI:10.1189/jlb.0510311