ROLE OF THE MITOGEN-ACTIVATED PROTEIN-KINASES AND TYROSINE KINASES DURING LEUKOTRIENE B-4 INDUCED EOSINOPHIL ACTIVATION

Exposure of guinea-pig eosinophils to leukotriene B-4 (LTB4; 1 mu M) r esulted in a rapid generation of H2O2 ((index of NADPH oxidase activat ion), stimulated [H-3]arachidonic acid (AA) release tinder of phosphol ipase 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-ter minal kinases 46 and 54 (JNK-46/54) or p38 mitogen-activated protein k inase (p38 MAP kinase). To examine the role of ERK-1/2 in the mechanis m of eosinophil activation, a selective inhibitor of MAP kinase kinase -1/2 (MEK-1/2), PD098059, was employed. However, PD 098059 at concentr ations that attenuated ERK-1/2 activation had no significant affect on eosinophil activation, In contrast, a role for tyrosine kinases in LT B4-induced eosinophil activation was suggested by studies with the tyr osine kinase inhibitors, herbimycin A and lavendustin A. However, the results of those experiments implied divergent pathways for the contro l of eosinophil responses because the inhibitors were more effective a t attenuating H2O2 generation than [H-3]AA release, and had little eff ect on homotypic aggregation.