title: CD45-induced tumor necrosis factor alpha production in monocytes is phosphatidylinositol 3-kinase-dependent and nuclear factor-kappaB-independent.
abstract: The pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha plays a pivotal role in the pathogenesis of rheumatoid arthritis. The mechanisms involved in regulating monocyte/macrophage TNFalpha production are not yet fully understood but are thought to involve both soluble factors and cell/cell contact with other cell types. Ligation of certain cell surface receptors, namely CD45, CD44, and CD58, can induce the production of TNFalpha in monocytes. In this paper, we investigate further the signaling pathways utilized by cell surface receptors (specifically CD45) to induce monocyte TNFalpha and compare the common/unique pathways involved with that of lipopolysaccharide. The results indicate that monocyte TNFalpha induced upon CD45 ligation or lipopolysaccharide stimulation is differentially modulated by phosphatidylinositol 3-kinase and nuclear factor-kappaB but similarly regulated by p38 mitogen-activated protein kinase. These results demonstrate that both common and unique signaling pathways are utilized by different stimuli for the induction of TNFalpha. These observations may have a major bearing on approaches to inhibiting TNFalpha production in disease where the cytokine has a pathogenic role.
authors.affiliation: Kennedy Institute of Rheumatology, Hammersmith, London W6 8LH, United Kingdom.
authors.forename: A L
authors.initials: AL
authors.lastname: Hayes
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.forename: B M
authors.initials: BM
authors.lastname: Foxwell
authors.forename: F M
authors.initials: FM
authors.lastname: Brennan
mesh_terms: D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D017493:Leukocyte Common Antigens; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019893:Ribosomal Protein S6 Kinases; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases