Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells.,Nature Chemical Biology

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Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells.
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2017-08-14 , 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}

Affiliation

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Center for the Development of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
Infectious Disease and Microbiome Program, Broad Institute, Cambridge, Massachusetts, USA.
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Department of Chemistry, Yale University, New Haven, Connecticut, USA.
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts, USA.
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
Howard Hughes Medical Institute, Cambridge, Massachusetts, USA.

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.

中文翻译：

小分子研究确定CDK8是髓样细胞中IL-10的调节剂。

增强抗炎细胞因子白介素10（IL-10）的产生是抑制病原性炎症的一种有前途的策略。为了确定调节IL-10产生的新机制，我们对增强激活树突状细胞的IL-10分泌的小分子进行了表型筛选。作用机理研究使用了优先筛选的结果BRD6989，确定了与介质相关的激酶CDK8及其旁系同源物CDK19，是先天性免疫激活过程中IL-10产生的负调节剂。BRD6989上调IL-10的能力通过多种结构上不同的CDK8和CDK19抑制剂得以概括，并且需要完整的细胞周期蛋白C-CDK8复合物。使用高度平行的通路报告基因检测我们确定了CDK8和CDK19抑制后，IL-10增强中AP-1活性增强的作用，该作用与c-Jun负调控位点的磷酸化减少有关。这些发现确定了CDK8和CDK19在调节先天性免疫激活中的功能，并暗示这些激酶可能值得考虑作为炎性疾病的治疗靶标。

更新日期：2017-09-08

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