title: CD40 ligation induces macrophage IL-10 and TNF-alpha production: differential use of the PI3K and p42/44 MAPK-pathways.
abstract: Interleukin 10 (IL-10) is an anti-inflammatory cytokine produced in the rheumatoid arthritis (RA) joint by macrophages/monocytes and infiltrating peripheral blood derived lymphocytes. Recent data suggest a role for physical cell-to-cell interactions in the production of IL-10. In this report, we have investigated the signalling mechanisms involved in IL-10 production by peripheral blood-derived macrophages upon interaction with fixed CD40L transfectants. IL-10 and tumour necrosis factor alpha (TNF-alpha) are produced by macrophage colony-stimulating factor (M-CSF)-primed monocytes/macrophages in response to CD40 ligation. The utilization of the inhibitors, wortmannin and LY294002, demonstrated a role for phosphatidylinositol 3-kinase (PI3K) whereas rapamycin demonstrated p70 S6-kinase (p70S6K) involvement in the production of IL-10 by these monocytes. The production of TNF-alpha was enhanced by wortmannin and LY294002, suggesting negative regulation by PI3K; however, it was dependent on p70S6K suggesting a PI3K-independent mechanism of p70S6K activation. One alternative pathway that activates p70S6K independently of PI3K and also differentiates between IL-10 and TNF-alpha is the p42/44 mitogen-activated protein kinase (MAPK), which regulates TNF-alpha production in a PI3K-independent manner. These observations suggest that CD40 ligation induces macrophage IL-10 and TNF-alpha production, the mechanism of which is p70S6K-dependent yet bifurcates at the level of PI3K and p42/44 MAPK.
authors.affiliation: Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, UK. a.foey@ic.ac.uk
authors.forename: A D
authors.initials: AD
authors.lastname: Foey
authors.forename: M
authors.initials: M
authors.lastname: Feldmann
authors.forename: F M
authors.initials: FM
authors.lastname: Brennan
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D019013:CD40 Antigens; D002867:Chromones; D009025:Morpholines; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D023201:CD40 Ligand; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D019893:Ribosomal Protein S6 Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000077191:Wortmannin