Regulation of macrophage interleukin-6 (IL-6) and IL-10 expression by prostaglandin E2: the role of p38 mitogen-activated protein kinase.
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.
Williams
J A
JA
Laboratory of Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda MD 20892, USA.
Pontzer
C H
CH
Shacter
E
E
D000818:Animals; D015232:Dinoprostone / Q000502:physiology*; D005260:Female; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
D015850:Interleukin-6; D016753:Interleukin-10; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone