MxA suppresses TAK1-IKK/-NF-B mediated inflammatory cytokine production to facilitate Mycobacterium tuberculosis infection
JOURNAL OF INFECTION(2020)
摘要
Objectives: Interferons (IFNs) play multifunctional roles in host defense against infectious diseases by inducing IFN-stimulated genes (ISGs). However, little is known about how ISGs regulate host immune response to Mycobacterium tuberculosis (Mtb) infection, the major cause of tuberculosis (TB). Methods: We thus profiled the potential effects and mechanisms of eight Mtb-induced ISGs on Mtb infection by RNA interference in human macrophages (W phi s) derived from peripheral blood monocytes (hMDMs) and THP-1 cell line derived W phi s (THP-1-W phi s). Results: MxA silencing significantly decreased intracellular Mtb infection in M phi s. Mechanistically, MxA silencing promoted inflammatory cytokines IL-1 beta, IL-6 and TNF-alpha production, and induced NF-kappa B p65 activation. Pharmacological inhibition of NF-kappa B p65 activation or gene silencing of NF-kappa B p65 blocked the increased production of IL-1 beta, IL-6 and TNF-alpha and restored Mtb infection by MxA silencing. Furthermore, pharmacological inhibition of TAK1 and IKK alpha/beta blocked NF-kappa B p65 activation and subsequent production of pro-inflammatory cytokines by MxA silencing. Isoniazid (INH) treatment and MxA silencing could promote TAK1-IKK alpha/beta-NF-kappa B signaling pathway activation and combat Mtb infection independently. Conclusions: Our results reveal a novel role of MxA in regulating TAK1-IKK alpha/beta-NF-kappa B signaling activation and production of antimicrobial inflammatory cytokines upon Mtb infection, providing a potential target for clinical treatment of TB. (C) 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
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关键词
Mycobacterium tuberculosis (Mtb),Myxovirus resistance protein 1 (MxA),Macrophages (M phi s),TGF-beta-activating kinase 1 (TAK1),I kappa B kinase alpha/beta (IKK alpha/beta),Nuclear factor-kappa B (NF-kappa B)
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