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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 00:00:00 , DOI: 10.1038/nchembio.2458
Liv Johannessen , Thomas B Sundberg , Daniel J O'Connell , Raivo Kolde , James Berstler , Katelyn J Billings , Bernard Khor , Brinton Seashore-Ludlow , Anne Fassl , Caitlin N Russell , Isabel J Latorre , Baishan Jiang , Daniel B Graham , Jose R Perez , Piotr Sicinski , Andrew J Phillips , Stuart L Schreiber , Nathanael S Gray , Alykhan F Shamji , Ramnik J Xavier

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的能力被多种结构上不同的CDK8和CDK19抑制剂概括,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:2017-09-20
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