Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells
| Autor: | Liv Johannessen, Andrew J. Phillips, Isabel J. Latorre, Thomas B. Sundberg, Alykhan F. Shamji, Nathanael S. Gray, James Berstler, José Carlos Rodríguez Pérez, Raivo Kolde, Ramnik J. Xavier, Daniel B. Graham, Caitlin N. Russell, Stuart L. Schreiber, Brinton Seashore-Ludlow, Anne Fassl, Bernard Khor, Katelyn J Billings, Daniel J. O’Connell, Piotr Sicinski, Baishan Jiang |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Phenotypic screening medicine.medical_treatment Regulator Inflammation Biology Article Small Molecule Libraries 03 medical and health sciences Mice Structure-Activity Relationship medicine Animals Humans Myeloid Cells Molecular Biology Cells Cultured Innate immune system Dose-Response Relationship Drug Molecular Structure Kinase Cell Biology Cyclin-Dependent Kinase 8 Cell biology Interleukin-10 Mice Inbred C57BL Interleukin 10 030104 developmental biology Cytokine medicine.symptom Chemical genetics |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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