CDK8/19 inhibitors induce M2-like macrophage polarization.

Macrophages polarize into anti-inflammatory macrophages (M2 macrophages) by interleukin (IL)-4, and these M2 macrophages express arginase-1. In addition, it has been reported that several cyclin-dependent kinase (CDK) 8/19 inhibitors promotes anti-inflammatory responses, and a number of CDK8/19 inhibitors have been developed. However, the effects of CDK8/19 inhibitors on arginase-1 expression in macrophages have not been clarified. In this study, we investigated the effects of CDK8/19 inhibitors on arginase-1 expression in murine macrophage cell line RAW264.7. The cells were pre-treated with BRD6989 or Senexin A, a CDK8/19 selective inhibitor, and then stimulated with IL-4. BRD6989 and Senexin A increased the IL-4-induced arginase-1 expression. Furthermore, we founded that p38 MAPK inhibitors suppressed the BRD6989-increased arginase-1 expression. On the other hands, BRD6989 and Senexin A increased the surface expression of CD206, a M2 macrophage marker, in RAW264.7 cells. In conclusion, we demonstrated for the first time that CDK8/19 inhibitors increased arginase-1 expression in macrophages via p38 MAPK activation. These findings suggest that CDK8/19 inhibition might induce anti-inflammatory M2-like macrophages.