title: Interleukin-17A differentially modulates BCG induction of cytokine production in human blood macrophages.
abstract: 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.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
authors.forename: J W
authors.initials: JW
authors.lastname: Fang
authors.forename: James C B
authors.initials: JC
authors.lastname: Li
authors.forename: K Y
authors.initials: KY
authors.lastname: Au
authors.forename: Howard C H
authors.initials: HC
authors.lastname: Yim
authors.forename: Allan S Y
authors.initials: AS
authors.lastname: Lau
mesh_terms: D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007113:Immunity, Innate; D020381:Interleukin-17 / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D009164:Mycobacterium Infections / Q000276:immunology; D009163:Mycobacterium bovis / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha