LYN, JAK2, AND RAF-1 KINASES ARE CRITICAL FOR THE ANTIAPOPTOTIC EFFECT OF INTERLEUKIN-5, WHEREAS ONLY RAF-1 KINASE IS ESSENTIAL FOR EOSINOPHIL ACTIVATION AND DEGRANULATION

Interleukin (IL)-5 has been shown to activate many signaling molecules in eosinophils, but their functional relevance remains unknown. We ha ve examined the functional relevance of Lyn, Jak2, and Raf-1 kinases i n eosinophil survival, upregulation of adhesion molecules and degranul ation. To this goal we used Lyn and Raf-1 antisense (AS) oligodeoxynuc leotides (ODN) to inhibit the expression of these proteins and tyrphos tin AG490 to specifically block the activation of Jak2. We have demons trated that all three kinases are important for IL-5-induced suppressi on of eosinophil apoptosis. However, Lyn and Jak2 tyrosine kinases are not important for the upregulation of CD11b and the secretion of eosi nophil cationic protein. In contrast, Raf-1 kinase is critical for bot h these functions. This is the first identification of specific signal ing molecules responsible for three important functions of eosinophils . We have established a central role for Raf-1 kinase in regulating eo sinophil survival, expression of beta(2) integrins and degranulation. Further, there appears to be a dissociation between two receptor-assoc iated tyrosine kinases, i.e., Lyn and Jak2, and the activation of Raf- l kinase. The delineation of the functional relevance of signaling mol ecules will help design therapeutic approaches targeting specific eosi nophil function.