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

Abstract

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.

• Authors: Xinying Zhou, Lijie Zhang, Linmiao Lie, Zelin Zhang, Bo Zhu, Jiahui Yang, Yuchi Gao, Pengfei Li, Yingqi Huang, Hui Xu, Yanfen Li, Xialin Du, Chaoying Zhou, Shengfeng Hu, Qian Wen, Xiao-Ping Zhong, Li Ma
• Journal: The Journal of infection (J Infect) Vol. 81 Issue 2 Pg. 231-241 (08 2020) ISSN: 1532-2742 [Electronic] England
• PMID: 32445727 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020. Published by Elsevier Ltd.

Chemical References

• Cytokines
• NF-kappa B
• I-kappa B Kinase

Topics

• Cytokines
• Humans
• I-kappa B Kinase (metabolism)
• Mycobacterium tuberculosis
• NF-kappa B (metabolism)
• Signal Transduction
• Tuberculosis