Involvement of JAK2, but not PI3-kinase/Akt and MAP kinase pathways, in anti-apoptotic signals of GM-CSF in human eosinophils

Granulocyte-macrophage colony-stimulating factor (GM-CSF) transmits anti-ap optotic signals in eosinophils and is involved in tissue eosinophilia at th e site of allergic inflammation. We determined whether phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinase (MAP kinase) a re involved in anti-apoptotic signals of GM--CSF in eosinophils. GM-CSF pho sphorylated Akt, a downstream component of PI 3-kinase, and MAP kinases (ER K1 and ERK2) at 10 min after stimulation in eosinophils. GM-CSF prevented e osinophil apoptosis and sustained its survival during the 5-day culture. Ho wever, neither two PI-3 kinase inhibitors, wortmannin and LY294002, nor MEK inhibitor PD98059 inhibited GM-CSF-induced survival of eosinophils, althou gh wortmannin and PD98059 inhibited GM-CSF-induced Akt phosphorylation and MAP kinase activation in eosinophils, respectively. In contrast, JAK2 inhib itor AG-490 inhibited both GM-CSF-induced JAK2 phosphorylation and cell sur vival in eosinophils. These results indicate that activation of JAK2, but n ot activation of PI 3-kinase/Akt and MAP kinase pathways, is critical for a nti-apoptotic signals of GM-CSF in human eosinophils. Our findings suggest that manipulation of JAK2 activation would be useful for the treatment of a llergic disorders.