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

Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-B 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-B 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-B-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 and IL-13 production and, under competing conditions, favored the differentiation of naïve CD4+ T cells into TH2 cells rather than TH17 cells. These results demonstrate that SMs shape the gene expression and protein profiles of TH17 cells and inhibit TH17 cell-driven autoimmunity.

Kaplinsky, JosephTechnical University of Denmark (författare)
Agerholm, RasmusTechnical University of Denmark (författare)
Kadekar, DarshanaTechnical University of Denmark (författare)
Ivars, FredrikLund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups(Swepub:lu)immu-fiv (författare)
Agace, William W.Lund University,Lunds universitet,Slemhinnans immunologi,Forskargrupper vid Lunds universitet,Mucosal Immunology,Lund University Research Groups,Technical University of Denmark(Swepub:lu)immu-wag (författare)
Wei-Lynn Wong, W.University Hospital of Zurich (författare)
Szucs, Matthew J.Broad Institute (författare)
Myers, Samuel A.Broad Institute (författare)
Carr, Steven A.Broad Institute (författare)
Waisman, AriUniversitätsmedizin Mainz (författare)
Bekiaris, VasileiosTechnical University of Denmark(Swepub:lu)med-veb (författare)
Technical University of DenmarkImmunologi (creator_code:org_t)

Ingår i:Science Signaling: American Association for the Advancement of Science (AAAS)12:5961945-08771937-9145

Av författaren/redakt...: Rizk, John; Kaplinsky, Josep ...; Agerholm, Rasmus; Kadekar, Darshan ...; Ivars, Fredrik; Agace, William W ...; visa fler...; Wei-Lynn Wong, W ...; Szucs, Matthew J ...; Myers, Samuel A.; Carr, Steven A.; Waisman, Ari; Bekiaris, Vasile ...; visa färre...

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