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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.

Original publication

DOI

10.1006/cyto.2001.0954

Type

Journal article

Journal

Cytokine

Publication Date

11/2001

Volume

16

Pages

131 - 142

Addresses

Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, UK. a.foey@ic.ac.uk

Keywords

Macrophages, Humans, Morpholines, Chromones, Androstadienes, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Ribosomal Protein S6 Kinases, Tumor Necrosis Factor-alpha, CD40 Ligand, Antigens, CD40, Interleukin-10, Transfection, Phosphatidylinositol 3-Kinases, In Vitro Techniques