MSK1 and MSK2 inhibit lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop.

Journal article

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 E2 (PGE2) levels following intraperitoneal injection of LPS.

Authors: MacKenzie, K; Van Den Bosch, M; Naqvi, S; Elcombe, SE; McGuire, V

• Publication status: Published
• Journal: Molecular and cellular biology
• Volume: 33
• Issue: 7
• Pages: 1456-1467
• Publication date: 2013-04-01
• DOI: 10.1128/MCB.01690-12
• EISSN: 1098-5549
• ISSN: 0270-7306
• Language: English
• Keywords: Prostaglandins; Proteolysis; Cyclooxygenase 2; Transcription, Genetic; Lipopolysaccharides; Cells, Cultured; Macrophages; Adaptor Proteins, Signal Transducing; Intracellular Signaling Peptides and Proteins; Interleukin-10; Mice; Toll-Like Receptors; p38 Mitogen-Activated Protein Kinases; Ribosomal Protein S6 Kinases, 90-kDa; Protein-Serine-Threonine Kinases; RNA Stability; RNA, Messenger; Mice, Inbred C57BL; Animals