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

• Published in: Nature chemical biology Vol. 13; no. 10; pp. 1102 - 1108
• Main Authors: Johannessen, Liv, Sundberg, Thomas B, O'Connell, Daniel J, Kolde, Raivo, Berstler, James, Billings, Katelyn J, Khor, Bernard, Seashore-Ludlow, Brinton, Fassl, Anne, Russell, Caitlin N, Latorre, Isabel J, Jiang, Baishan, Graham, Daniel B, Perez, Jose R, Sicinski, Piotr, Phillips, Andrew J, Schreiber, Stuart L, Gray, Nathanael S, Shamji, Alykhan F, Xavier, Ramnik J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2017; Nature Publishing Group
• Subjects: 13/106; 38/39; 631/250; 631/92/275; 631/92/555; 631/92/93; 64/110; 96/95; Activation; Animals; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; c-Jun protein; Cell Biology; Cells; Cells, Cultured; Chemistry; Chemistry/Food Science; Cyclin C; Cyclin-Dependent Kinase 8 - immunology; Cyclin-Dependent Kinase 8 - metabolism; Cytokines; Dendritic cells; Dose-Response Relationship, Drug; Humans; Inflammation; Inflammatory diseases; Interleukin 10; Interleukin-10 - biosynthesis; Interleukin-10 - immunology; Kinases; Mice; Mice, Inbred C57BL; Molecular Structure; Molecules; Myeloid cells; Myeloid Cells - drug effects; Myeloid Cells - immunology; Myeloid Cells - metabolism; Pathogens; Phosphorylation; Regulators; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Transcription factors
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.2458

Editorial Summary Inhibitors of CDK8 enhance IL-10 production during innate immune activation in human and mouse primary macrophages and dendritic cells via diminished phosphorylation of the c-Jun subunit of the AP-1 transcription regulatory complex. 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.