CD45-induced tumor necrosis factor α production in monocytes is phosphatidylinositol 3-kinase-dependent and nuclear factor-κB-independent

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 TNF alpha 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 TNF alpha in monocytes. In this paper, we investigate further the signaling pathways utilized by cell surface receptors (specifically CD45) to induce monocyte TNF alpha and compare the common/unique pathways involved with that of lipopolysaccharide. The results indicate that monocyte TNF alpha induced upon CD45 ligation or lipopolysaccharide stimulation is differentially modulated by phosphatidylinositol 3-kinase and nuclear factor-kappa B 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 TNF alpha. These observations may have a major bearing on approaches to inhibiting TNF alpha production in disease where the cytokine has a pathogenic role.