SMAC mimetics promote NIK-dependent inhibition of CD4+ TH17 cell differentiation.

SMAC mimetics promote NIK-dependent inhibition of CD4+ TH17 cell differentiation. Sci Signal. 2019 Aug 27;12(596): Authors: Rizk J, Kaplinsky J, Agerholm R, Kadekar D, Ivars F, Agace WW, Wong WW, Szucs MJ, Myers SA, Carr SA, Waisman A, Bekiaris V Abstract Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-κB signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4+ T cells with SMs during T helper 17 (TH17) cell differentiation disrupted the balance between two antagonistic transcription factor modules. Moreover, proteomics analysis revealed that SMs altered the abundance of proteins associated with cell cycle, mitochondrial activity, and the balance between canonical and noncanonical NF-κB signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated TH17 cell-driven inflammation, they stimulated IL-22 secretion. Mechanistically, SM-mediated activation of NF-κB-inducing kinase (NIK) and the transcription factors RelB and p52 directly suppressed Il17a expression and IL-17A protein production, as well as the expression of a number of other immune genes. Induction of IL-22 production correlated with the NIK-dependent reduction in cMAF protein abundance and the enhanced activity of the aryl hydrocarbon receptor. Last, SMs also increased IL-9 an...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research