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

Regulation by the p38 mitogen-activated protein (MAP) kinase signaling path way of monocytic inflammatory functions was evaluated using L-790,070, a po tent and selective inhibitor of p38 MAP kinase, Three major functions of mo nocytes 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 prote in-1 alpha (MIP-1 alpha), monocyte chemotactic protein-1 (MCP-1), and fMLP were all sensitive to L-790,070, When titrated, L-790,070 inhibited MCP-1-i nduced chemotaxis in a concentration-dependent manner with an IC50 of 0.3 n M, However, the ability of serum-derived macrophages to phagocytose apoptot ic neutrophils was unaffected by L-790,070, The concentration with which L- 790,070 inhibited both differentiation and chemotaxis was similar to that n ecessary 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 diffe rentiation and prevented chemotaxis was by inhibiting p38 MAP kinase activi ty.