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Nat Chem Biol DOI:10.1038/nchembio.2458

Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells.

Publication TypeJournal Article
Year of Publication2017
AuthorsJohannessen, iv, L, Sundberg, TB, O'Connell, DJ, Kolde, R, Berstler, J, Billings, KJ, Khor, B, Seashore-Ludlow, B, Fassl, A, Russell, CN, Latorre, IJ, Jiang, B, Graham, DB, Perez, JR, Sicinski, P, Phillips, AJ, Schreiber, SL, Gray, NS, Shamji, AF, Xavier, RJ
JournalNat Chem Biol
Date Published2017 Oct
KeywordsAnimals, Cells, Cultured, Cyclin-Dependent Kinase 8, Dose-Response Relationship, Drug, Humans, Interleukin-10, Mice, Mice, Inbred C57BL, Molecular Structure, Myeloid Cells, Small Molecule Libraries, Structure-Activity Relationship

Enhancing production of the anti-inflammatory cytokine interleukin-10 (IL-10) is a promising strategy to suppress pathogenic inflammation. To identify new mechanisms regulating IL-10 production, we conducted a phenotypic screen for small molecules that enhance IL-10 secretion from activated dendritic cells. Mechanism-of-action studies using a prioritized hit from the screen, BRD6989, identified the Mediator-associated kinase CDK8, and its paralog CDK19, as negative regulators of IL-10 production during innate immune activation. The ability of BRD6989 to upregulate IL-10 is recapitulated by multiple, structurally differentiated CDK8 and CDK19 inhibitors and requires an intact cyclin C-CDK8 complex. Using a highly parallel pathway reporter assay, we identified a role for enhanced AP-1 activity in IL-10 potentiation following CDK8 and CDK19 inhibition, an effect associated with reduced phosphorylation of a negative regulatory site on c-Jun. These findings identify a function for CDK8 and CDK19 in regulating innate immune activation and suggest that these kinases may warrant consideration as therapeutic targets for inflammatory disorders.


Alternate JournalNat. Chem. Biol.
PubMed ID28805801
PubMed Central IDPMC5693369
Grant ListP30 DK043351 / DK / NIDDK NIH HHS / United States
U01 DK062432 / DK / NIDDK NIH HHS / United States
T32 CA009216 / CA / NCI NIH HHS / United States
K08 DK104021 / DK / NIDDK NIH HHS / United States
T32 CA009361 / CA / NCI NIH HHS / United States
R01 CA190509 / CA / NCI NIH HHS / United States