Regulation of Macrophage Interleukin-6 (IL-6) and IL-10 Expression by Prostaglandin E 2 : The Role of p38 Mitogen-Activated Protein Kinase

Abstract

Prostaglandin E₂ (PGE₂) regulates production of a wide array of cytokines. We have found that PGE₂ can upregulate the levels of both interleukin-10 (IL-10) and IL-6 produced by activated murine macrophages, but the molecular pathways leading to their augmentation differ. Synthesis of IL-10 in response to PGE₂ is dependent on p38 MAP kinase activity, whereas synthesis of IL-6 is not. Evidence to support this derives from two experimental approaches. First, we established that PGE₂ is effective in elevating IL-10 levels only when it is added to cells in which p38 kinase has been activated. In contrast, PGE₂ can augment IL-6 levels regardless of whether or not p38 kinase is active. Second, we showed that inhibitors that are selective for p38 kinase prevent the IL-10 response to PGE₂ but not the IL-6 response. We found that p38 kinase inhibitors are able to inhibit IL-6 production in activated macrophages, but this occurs primarily as a result of their concurrent inhibition of cyclooxygenase-2 and endogenous PGE₂ synthesis. These results indicate that macrophage IL-10 and IL-6 expression is differentially regulated by PGE₂ and p38 MAP kinase in murine inflammatory macrophages.