Abstract：
Macrophages polarize into alternatively activated M2 macrophages through interleukin (IL)-4, and they express high levels of arginase-1, which promotes anti-inflammatory responses. Several studies have confirmed the anti-inflammatory effects of cyclin-dependent kinase (CDK) 8/19 inhibition, and hence, numerous CDK8/19 inhibitors, such as BRD6989, have been developed. However, the effects of CDK8/19 inhibitors on arginase-1 expression in macrophages have not yet been elucidated. This study investigated the effects of CDK8/19 inhibitor on arginase-1 expression in IL-4-activated macrophages. The results showed that BRD6989 increased arginase-1 expression transcriptionally in murine peritoneal macrophages and the murine macrophage cell line RAW264.7 in an IL-4-dependent manner. In addition, the results indicated that BRD6989 enhances signal transducer and activator of transcription (STAT) 6 phosphorylation. Meanwhile, BRD6989 exhibited the capability to activate p38 mitogen-activated protein kinase (MAPK） even in the absence of IL-4 stimulation. Moreover, we observed that a p38 MAPK inhibitor suppressed the BRD6989-induced increase in arginase-1 expression. Besides, BRD6989 increased the surface expression of CD206, an M2 macrophage marker. Thus, this study demonstrated for the first time that CDK8/19 inhibition increases arginase-1 expression, suggesting that this mechanism involves the activation of STAT6 and p38 MAPK. This finding implies that CDK8/19 inhibition may facilitate the production of anti-inflammatory M2 macrophages.
摘要：
巨噬细胞通过白细胞介素（IL）-4极化成交替激活的M2巨噬细胞，它们表达高水平的精氨酸酶-1，从而促进抗炎反应。一些研究证实了细胞周期蛋白依赖性激酶（CDK）8/19抑制的抗炎作用，因此，许多CDK8/19抑制剂，如BRD6989，已开发。然而,CDK8/19抑制剂对巨噬细胞精氨酸酶-1表达的影响尚未阐明.这项研究调查了CDK8/19抑制剂对IL-4激活的巨噬细胞中精氨酸酶-1表达的影响。结果表明，BRD6989以IL-4依赖性方式在小鼠腹膜巨噬细胞和小鼠巨噬细胞系RAW264.7中转录增加精氨酸酶-1的表达。此外,结果表明，BRD6989增强了信号转导和转录激活因子（STAT）6的磷酸化。同时,BRD6989即使在没有IL-4刺激的情况下也显示出激活p38丝裂原活化蛋白激酶（MAPK）的能力。此外，我们观察到p38MAPK抑制剂抑制了BRD6989诱导的精氨酸酶-1表达的增加。此外,BRD6989增加了M2巨噬细胞标记物CD206的表面表达。因此，这项研究首次证明了CDK8/19抑制增加了精氨酸酶-1的表达，提示该机制涉及STAT6和p38MAPK的激活。该发现暗示CDK8/19抑制可以促进抗炎M2巨噬细胞的产生。
