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
  • 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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