Role of the mitogen-activated protein kinases and tyrosine kinases during leukotriene B4 induced eosinophil activation

Exposure of guinea-pig eosinophils to leukotriene B-4 (LTB4; 1 mu M) resulted in a rapid generation of H2O2 ((index of NADPH oxidase activation), stimulated [H-3]arachidonic acid (AA) release tinder of phospholipase Az activity), and promoted CD18-dependent homotypic aggregation. Under similar conditions, LTB4 (1 mu M) induced a rapid activation of extracellular-regulated kinases-l and 2 (ERK-1/2) but not c-jun N-terminal kinases 46 and 54 (JNK-46/54) or p38 mitogen-activated protein kinase (p38 MAP kinase). To examine the role of ERK-1/2 in the mechanism of eosinophil activation, a selective inhibitor of MAP kinase kinase-1/2 (MEK-1/2), PD098059, was employed. However, PD 098059 at concentrations that attenuated ERK-1/2 activation had no significant affect on eosinophil activation, In contrast, a role for tyrosine kinases in LTB4-induced eosinophil activation was suggested by studies with the tyrosine kinase inhibitors, herbimycin A and lavendustin A. However, the results of those experiments implied divergent pathways for the control of eosinophil responses because the inhibitors were more effective at attenuating H2O2 generation than [H-3]AA release, and had little effect on homotypic aggregation.