REQUIREMENT OF LYN AND SYK TYROSINE KINASES FOR THE PREVENTION OF APOPTOSIS BY CYTOKINES IN HUMAN EOSINOPHILS

In allergic diseases, the cytokines interleukin (IL)5 and granulocyte/ macrophage colony-stimulating factor (GM-CSF) are upregulated and have been proposed to cause blood and tissue eosinophilia by inhibition of eosinophil apoptosis. We demonstrate herein, in freshly isolated huma n eosinophils, that the IL-3/IL-5/GM-CSF receptor beta subunit interac ts with cytoplasmic tyrosine kinases to induce phosphorylation of seve ral cellular substrates, including the beta subunit itself. The Lyn an d Syk intracellular tyrosine kinases constitutively associate at a low level with the IL-3/IL-5/GM-CSF receptor beta subunit in human eosino phils. Stimulation with GM-CSF or IL-5 results in a rapid and transien t increase in the amount of Lyn and Syk associated with the IL-3/IL-5/ GM-CSF receptor beta subunit. Lyn is required for optimal tyrosine pho sphorylation and activation of Syk. In contrast, Syk is not required f or optimal tyrosine phosphorylation and activation of Lyn. These data suggest that Lyn is proximal to Syk in a tyrosine kinase cascade that transduces IL-3, IL-5, or GM-CSF signals. Compatible with this model, both Lyn and Syk are essential for the activation of the antiapoptotic pathway(s) induced through the IL-3/IL-5/GM-CSF receptor beta subunit in human eosinophils.