Macrophages polarize into anti-inflammatory macrophages by interleukin (IL)-4, and they express arginase-1. Arginase-1 promotes the function of anti-inflammatory macrophages and is crucial for maintaining tissue homeostasis. Both cyclin-dependent kinase (CDK) 8 and its paralog CDK19 are members of the transcriptional CDK family. CDK8/19 inhibitors have garnered attention as novel drugs for autoimmune diseases. However, the role of CDK8/19 inhibitors in IL-4-induced anti-inflammatory macrophage function remains unclear. In this study, we examined the effects of the CDK8/19 inhibitor BRD6989 on IL-4-induced arginase-1 expression.
RAW264.7 cells were pretreated with BRD6989, followed by stimulation with IL-4. BRD6989 enhanced IL-4-induced arginase-1 expression. Moreover, the increase in arginase-1 expression by BRD6989 was inhibited by the p38 MAPK inhibitor SB203580. On the other hand, BRD6989 increased the expression of phosphorylated p38 MAPK following IL-4 stimulation compared to the control. We then examined mRNA expression of C/EBPβ and found that BRD6989 increases C/EBPβ mRNA expression in comparison to controls. In summary, inhibition of CDK8/19 was found to contribute to the enhancement of IL-4-induced arginase-1 expression through the activation of p38 MAPK, suggesting the involvement of C/EBPβ as a signaling pathway. Elucidating the role of CDK8/19 in the regulation of arginase-1 expression is believed to contribute to the development of novel methods for inducing anti-inflammatory macrophages.