MxA suppresses TAK1-IKKα/β-NF-κB mediated inflammatory cytokine production to facilitate Mycobacterium tuberculosis infection.


Journal Article

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 (Mφs) derived from peripheral blood monocytes (hMDMs) and THP-1 cell line derived Mφs (THP-1-Mφs). RESULTS: MxA silencing significantly decreased intracellular Mtb infection in Mφs. Mechanistically, MxA silencing promoted inflammatory cytokines IL-1β, IL-6 and TNF-α production, and induced NF-κB p65 activation. Pharmacological inhibition of NF-κB p65 activation or gene silencing of NF-κB p65 blocked the increased production of IL-1β, IL-6 and TNF-α and restored Mtb infection by MxA silencing. Furthermore, pharmacological inhibition of TAK1 and IKKα/β blocked NF-κB p65 activation and subsequent production of pro-inflammatory cytokines by MxA silencing. Isoniazid (INH) treatment and MxA silencing could promote TAK1-IKKα/β-NF-κB signaling pathway activation and combat Mtb infection independently. CONCLUSIONS: Our results reveal a novel role of MxA in regulating TAK1-IKKα/β-NF-κB signaling activation and production of antimicrobial inflammatory cytokines upon Mtb infection, providing a potential target for clinical treatment of TB.

Full Text

Duke Authors

Cited Authors

  • Zhou, X; Zhang, L; Lie, L; Zhang, Z; Zhu, B; Yang, J; Gao, Y; Li, P; Huang, Y; Xu, H; Li, Y; Du, X; Zhou, C; Hu, S; Wen, Q; Zhong, X-P; Ma, L

Published Date

  • August 2020

Published In

Volume / Issue

  • 81 / 2

Start / End Page

  • 231 - 241

PubMed ID

  • 32445727

Pubmed Central ID

  • 32445727

Electronic International Standard Serial Number (EISSN)

  • 1532-2742

Digital Object Identifier (DOI)

  • 10.1016/j.jinf.2020.05.030


  • eng

Conference Location

  • England