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Interleukin‐32ε induces caspase‐independent apoptosis mediated by N‐Myc interactor in macrophages infected with Mycobacterium tuberculosis
Author(s) -
Li Zhongxia,
Wang Yizhi,
Liu Xin,
Xing Xupeng,
Zhang Yong
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14717
Subject(s) - apoptosis , biology , mycobacterium tuberculosis , downregulation and upregulation , proinflammatory cytokine , transcription factor , gene isoform , microbiology and biotechnology , immunology , tuberculosis , inflammation , gene , medicine , genetics , pathology
Mycobacterium tuberculosis ( Mtb ) is the pathogen responsible for tuberculosis, a leading cause of illness and death worldwide. Growing evidence suggests that the proinflammatory cytokine IL ‐32 plays a major role in host defences against pathogens such as Mtb . IL ‐32 exists in six alternatively spliced isoforms, but antituberculosis effects have been reported only for some of them. In this study, we examined the effect of all six IL ‐32 isoforms on Mtb replication in the murine macrophage cell line RAW 264.7. Compared with cells transfected with the other isoforms, IL ‐32ε‐transfected cells exhibited the strongest antituberculosis effect and the highest rate of Mtb‐ induced apoptosis. Of note, this apoptosis pathway was independent of caspase‐3 activation. Instead, N‐Myc interactor ( NMI ), an inhibitor of Wnt signalling, was a key player in IL ‐32ε‐mediated apoptosis by inhibiting Wnt/β‐catenin signalling and thereby activating c‐Myc‐mediated apoptosis. Moreover, we identified two cis ‐acting elements that are binding sites for the transcriptional regulators paired box 6 ( PAX 6) and transcription factor CP 2 ( TFCP 2) in the promoter of NMI and these elements proved essential for IL ‐32ε‐induced upregulation of Nmi expression. Furthermore, IL ‐32ε‐mediated activation of the mitogen‐activated protein kinase p38 also contributed to NMI upregulation. In conclusion, our results demonstrate that Mtb infection‐induced IL ‐32ε‐mediated apoptosis in macrophages plays a key role in host defences against Mtb .