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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
Volume13
Issue10
Pages1102-1108
Date Published2017 Oct
ISSN1552-4469
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
Abstract

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.

DOI10.1038/nchembio.2458
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28805801?dopt=Abstract

Alternate JournalNat. Chem. Biol.
PubMed ID28805801
Grant ListP30 DK043351 / DK / NIDDK NIH HHS / United States