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

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

  • Nat Chem Biol. 2017 Oct;13(10):1102-1108. doi: 10.1038/nchembio.2458.
Liv Johannessen 1 2,  Thomas B Sundberg 3,  Daniel J O'Connell 4,  Raivo Kolde 5,  James Berstler 3,  Katelyn J Billings 6 7,  Bernard Khor 5,  Brinton Seashore-Ludlow 7,  Anne Fassl 2 8,  Caitlin N Russell 9,  Isabel J Latorre 4,  Baishan Jiang 1 2,  Daniel B Graham 4 10,  Jose R Perez 3,  Piotr Sicinski 2 8,  Andrew J Phillips 3,  Stuart L Schreiber 7 11 12,  Nathanael S Gray 1 2,  Alykhan F Shamji 7,  Ramnik J Xavier 4 5 9
Affiliations

Affiliations

  • 1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 3 Center for the Development of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
  • 4 Infectious Disease and Microbiome Program, Broad Institute, Cambridge, Massachusetts, USA.
  • 5 Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • 6 Department of Chemistry, Yale University, New Haven, Connecticut, USA.
  • 7 Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
  • 8 Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
  • 9 Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • 10 Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 11 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
  • 12 Howard Hughes Medical Institute, Cambridge, Massachusetts, USA.
PMID: 28805801 DOI: 10.1038/nchembio.2458
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.

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