Role of interleukin-8 phosphorylated kinases in stimulating neutrophil migration through fibrin gels

Interleukin (IL)-8 elicits neutrophil migration in the early inflammatory r esponse. This action of IL-8 is believed to involve mitogen-activated prote in (MAP) kinase p44/42. In the present study, we used specific inhibitors t o investigate the role of p44/42 kinase in stimulating neutrophil migration . The IL-8-guided migration through an imitation of inflammatory matrix, a fibrin gel, was impaired by 90% after treatment with 7 mu M U0126, a specif ic inhibitor of the kinase of p44/42 kinase. Superoxide anion generation in duced by high concentrations of bacterial signals was not impaired in the a bsence of functional p44/42. This anion generation could be decoupled from the p44/42 independency by priming the cells, a pretreatment with IL-8. The addition of U0126 inhibited by 60% the priming and subsequent superoxide a nion generation triggered by low concentrations of bacterial signals. An im pact on the priming effect and migration of neutrophils was found upon bloc kade (with wortmannin) of a further kinase event that converges on the p44/ 42 phosphorylation. Wortmannin blocked phosphatidylinositol 3-kinase and se condarily phosphorylation of p44/42 and of the p44/42-related MAP kinase p3 8. The overlapping functional consequences of a specific blockade of p38 MA P kinase (applying in vivo anti-inflammatory pyridinyl imidazole) further a scribed a migratory role to those signals culminating in p44/42 MAP kinase phosphorylation, and suggests a role in vivo.