Serum-induced monocyte differentiation and monocyte chemotaxis are regulated by the p38 MAP kinase signal transduction pathway

Abstract

Regulation by the p38 mitogen-activated protein (MAP) kinase signaling pathway of monocytic inflammatory functions was evaluated using L-790,070, a potent and selective inhibitor of p38 MAP kinase. Three major functions of monocytes were investigated: differentiation, chemotaxis, and phagocytosis. L-790,070 inhibited serum-induced monocyte differentiation with an IC50 of 0.5 nM. Monocyte chemotaxis induced by RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemotactic protein- (MCP-1), and fMLP were all sensitive to L-790,070. When titrated, L-790,070 inhibited MCP-1-induced chemotaxis in a concentration-dependent manner with an IC50 of 0.3 nM. However, the ability of serum-derived macrophages to phagocytose apoptotic neutrophils was unaffected by L-790,070. The concentration with which L-790,070 inhibited both differentiation and chemotaxis was similar to that necessary to inhibit p38 MAP kinase activation of MAPKAP kinase (0.3 nM) in response to stimulation by lipopolysaccharide. Therefore, the data in this report suggest that the mechanism by which L-790,070 blocked monocyte differentiation and prevented chemotaxis was by inhibiting p38 MAP kinase activity.