MSK1 and MSK2 Inhibit Lipopolysaccharide-Induced Prostaglandin Production via an Interleukin-10 Feedback Loop

作者：MacKenzie Kirsty F; Van den Bosch Mirjam W M; Naqvi Shaista; Elcombe Suzanne E; McGuire Victoria A; Reith Alastair D; Blackshear Perry J; Dean Jonathan L E; Arthur J Simon C^*

来源：Molecular and Cellular Biology, 2013, 33(7): 1456-1467.

DOI：10.1128/MCB.01690-12

Prostaglandin production is catalyzed by cyclooxygenase 2 (cox-2). We demonstrate here that MSK1 and MSK2 (MSK1/2) can exert control on the induction of cox-2 mRNA by Toll-like receptor (TLR) agonists. In the initial phase of cox-2 induction, MSK1/2 knockout macrophages confirmed a role for MSK in the positive regulation of transcription. However, at later time points both lipopolysaccharide (LPS)-induced prostaglandin and cox-2 protein levels were increased in MSK1/2 knockout. Further analysis found that while MSKs promoted cox-2 mRNA transcription, following longer LPS stimulation MSKs also promoted degradation of cox-2 mRNA. This was found to be the result of an interleukin 10 (IL-10) feedback mechanism, with endogenously produced IL-10 promoting cox-2 degradation. The ability of IL-10 to do this was dependent on the mRNA binding protein TTP through a p38/MK2-mediated mechanism. As MSKs regulate IL-10 production in response to LPS, MSK1/2 knockout results in reduced IL-10 secretion and therefore reduced feedback from IL-10 on cox-2 mRNA stability. Following LPS stimulation, this increased mRNA stability correlated to an elevated induction of both of cox-2 protein and prostaglandin secretion in MSK1/2 knockout macrophages relative to that in wild-type cells. This was not restricted to isolated macrophages, as a similar effect of MSK1/2 knockout was seen on plasma prostaglandin E-2 (PGE(2)) levels following intraperitoneal injection of LPS.

• 出版日期2013-4