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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 defenses against pathogens such as Mtb. IL-32 exists in six alternatively spliced isoforms, but anti-tuberculosis 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 anti-tuberculosis 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 signaling, was a key player in IL-32ε-mediated apoptosis by inhibiting Wnt/β-catenin signaling 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 (PAX6) and transcription factor CP2 (TFCP2) 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 defenses against Mtb. This article is protected by copyright. All rights reserved.
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Name: The FEBS journal
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An inhibitor of apoptosis protein that is translated by a rare cap-independent mechanism. It blocks caspase-mediated cellular destruction by inhibiting CASPASE 3; CASPASE 7; and CASPASE 9.
A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 7; CASPASE 8; and CASPASE 10. Isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
A long pro-domain caspase that has specificity for the precursor form of INTERLEUKIN-1BETA. It plays a role in INFLAMMATION by catalytically converting the inactive forms of CYTOKINES such as interleukin-1beta to their active, secreted form. Caspase 1 is referred as interleukin-1beta converting enzyme and is frequently abbreviated ICE.
A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 3 and CASPASE 10. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
An APOPTOSIS-regulating protein that is structurally related to CASPASE 8 and competes with CASPASE 8 for binding to FAS ASSOCIATED DEATH DOMAIN PROTEIN. Two forms of CASP8 and FADD-like apoptosis regulating protein exist, a long form containing a caspase-like enzymatically inactive domain and a short form which lacks the caspase-like domain.