CD45-induced tumor necrosis factor alpha production in monocytes is phosphatidylinositol 3-kinase-dependent and nuclear factor-kappa B-independent

The pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha plays a piv otal role in the pathogenesis of rheumatoid arthritis. The mechanisms invol ved in regulating monocyte/macrophage TNF alpha production are not yet full y 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 TNF alpha in mono cytes. In this paper, we investigate further the signaling pathways utilize d by cell surface receptors (specifically CD45) to induce monocyte TNF alph a and compare the common/unique pathways involved with that of lipopolysacc haride. The results indicate that monocyte TNF alpha induced upon CD45 liga tion or lipopolysaccharide stimulation is differentially modulated by phosp hatidylinositol 3-kinase and nuclear factor-kappa B but similarly regulated by p38 mitogen-activated protein kinase. These results demonstrate that bo th common and unique signaling pathways are utilized by different stimuli f or the induction of TNF alpha. These observations may have a major bearing on approaches to inhibiting TNF alpha production in disease where the cytok ine has a pathogenic role.