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. Epub 2017 Aug 14.

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.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclin-Dependent Kinase 8 / immunology
  • Cyclin-Dependent Kinase 8 / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Interleukin-10 / biosynthesis*
  • Interleukin-10 / immunology
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Myeloid Cells / drug effects*
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • IL10 protein, mouse
  • Small Molecule Libraries
  • Interleukin-10
  • CDK8 protein, human
  • Cdk8 protein, mouse
  • Cyclin-Dependent Kinase 8

Associated data

  • PubChem-Substance/340134876
  • PubChem-Substance/340134887
  • PubChem-Substance/340134891
  • PubChem-Substance/340134892
  • PubChem-Substance/340134893
  • PubChem-Substance/340134894
  • PubChem-Substance/340134895
  • PubChem-Substance/340134896
  • PubChem-Substance/340134897
  • PubChem-Substance/340134877
  • PubChem-Substance/340134878
  • PubChem-Substance/340134879
  • PubChem-Substance/340134880
  • PubChem-Substance/340134881
  • PubChem-Substance/340134882
  • PubChem-Substance/340134883
  • PubChem-Substance/340134884
  • PubChem-Substance/340134885
  • PubChem-Substance/340134886
  • PubChem-Substance/340134888
  • PubChem-Substance/340134889
  • PubChem-Substance/340134890