LPS-dependent cyclooxygenase-2 induction in human monocytes is down-regulated by IL-13, but not by IFN-gamma.
We investigated the effects of Th2 cell-associated cytokines, IL-4, IL-10, and IL-13, on prostaglandin (PG) production by human peripheral blood monocytes (HPBM) in terms of four parameters: PGE2 synthesis; cyclooxygenase activity; protein; and mRNA of two cyclooxygenase isozymes (cyclooxygenase-1 and cyclooxygenase-2). LPS-stimulated PGE2 synthesis and cyclooxygenase activity were suppressed by IL-4, IL-10, or IL-13. Furthermore, the LPS-dependent increase of cyclooxygenase activity in HPBM was attributable to cyclooxygenase-2 because it was inhibited by NS-398 (a cyclooxygenase-2-specific inhibitor). Western and Northern blot analyses revealed that the LPS-induced increases in cyclooxygenase-2 protein and mRNA were attenuated by the addition of IL-4, IL-10, or IL-13. In contrast, cyclooxygenase-1 protein and mRNA were hardly detected in monocytes that were incubated with or without LPS in the presence or absence of IL-4, IL-10, and IL-13. These results suggest that the reduction of LPS-induced PGE2 synthesis and cyclooxygenase activity by IL-4, IL-10, and IL-13 in HPBM are mainly due to the down-regulation of cyclooxygenase-2 selectively induced by LPS. Conversely, IFN-gamma, a Th1 cell-associated cytokine, did not affect PGE2 production and cyclooxygenase activity. These data suggest a mechanism for modulation of inflammation by the anti-inflammatory Th2 cell-associated cytokines but not a Th1 cell-associated cytokine.
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Third Department of Internal Medicine, School of Medicine, Tokushima University, Japan.
Ogushi
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Sone
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D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D004790:Enzyme Induction / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology*; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D018793:Interleukin-13; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone