Regulation of macrophage interleukin-6 (IL-6) and IL-10 expression by prostaglandin E-2: The role of p38 mitogen-activated protein kinase

Prostaglandin E-2 (PGE(2)) regulates production of a wide array of cytokines, We have found that PGE(2) 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 PGE(2) is dependent on p38 MAP kinase activity, whereas synthesis of IL-6 is not. Evidence to support this derives from two experimental approaches. First, me established that PGE(2) is effective in elevating IL-10 levels only when it is added to cells in which p38 kinase has been activated. In contrast, PGE(2) 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 PGE(2) 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 PGE(2) synthesis. These results indicate that macrophage IL-10 and IL-6 expression is differentially regulated by PGE(2) and p38 MAP kinase in murine inflammatory macrophages.