P38 mitogen activated protein kinase is involved in the downregulation of granulocyte CXC chemokine receptors 1 and 2 during human endotoxemia

Chemokine receptors CXC receptor (CXCR) 1 and 2, and their ligands interleukin (IL)-8 and growth-related oncogene alpha (GRO alpha), are principal regulators of neutrophil activation and migration. To investigate the role of p38 mitogen activated protein kinase( MAPK) in the regulation of CXCR expression during an inflammatory response in vivo, 24 healthy volunteers received an intravenous injection with lipopolysaccharide (LPS) preceded (-3 hr) by a specific p38 MAPK inhibitor (BIRB 796 BS) at a high dose (600 mg) or a low dose (50 mg) or a placebo. The LPS-induced reduction of neutrophil CXCR 1 and 2 expression, as determined by fluorescence-activated cell sorter analysis, was inhibited in volunteers receiving the high dose of the p38 MAPK inhibitor. The kinase inhibitor also dose dependently diminished the LPS-induced rises in plasma IL-8 and GROalpha levels. These results indicate a principal role for p38 MAPK in regulating factors essential for neutrophil activation and chemotaxis in vivo