Involvement of JAK2, but not PI 3-kinase/Akt and MAP kinase pathways, in anti-apoptotic signals of GM-CSF in human eosinophils

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) transmits anti-apoptotic signals in eosinophils and is involved in tissue eosinophilia at the site of allergic inflammation. We determined whether phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinase (MAP kinase) are involved in anti-apoptotic signals of GM-CSF in eosinophils. GM-CSF phosphorylated Akt, a downstream component of PI 3-kinase, and MAP kinases (ERK1 and ERK2) at 10 min after stimulation in eosinophils. GM-CSF prevented eosinophil apoptosis and sustained its survival during the 5-day culture. However, neither two PI-3 kinase inhibitors, wortmannin and LY294002, nor MEK inhibitor PD98059 inhibited GM-CSF-induced survival of eosinophils, although wortmannin and PD98059 inhibited GM-CSF-induced Akt phosphorylation and MAP kinase activation in eosinophils, respectively. In contrast, JAK2 inhibitor AG-490 inhibited both GM-CSF-induced JAK2 phosphorylation and cell survival in eosinophils. These results indicate that activation of JAK2, but not activation of PI 3-kinase/Akt and MAP kinase pathways, is critical for anti-apoptotic signals of GM-CSF in human eosinophils. Our findings suggest that manipulation of JAK2 activation would be useful for the treatment of allergic disorders. J. Leukoc. Biol. 65: 700-706; 1999.

Transduction of a dominant-negative H-Ras into human eosinophils attenuates extracellular signal–regulated kinase activation and interleukin-5–mediated cell viability

“…Previous studies using blood eosinophils have reported conflicting data on whether the Ras-Raf-MEK-ERK pathway is important in eosinophil survival. Based on the use of a chemical inhibitor of MEK 1 (PD98059), a previous study by Miike et al 37 reported that ERK activity is not necessary for IL-5-stimulated blood eosinophil survival, and we have recapitulated those data ( Figure 8). Another study has implicated c-Raf-1 as important in eosinophil-mediated survival but not in ERK activation.…”

“…A comparable concentration of Tat-GFP protein did not inhibit IL-5-mediated survival during the same period of time, again revealing the selectivity of Tat-dn-H-Ras. In addition, as previously reported, 37 the MEK 1 antagonist PD98059 did not inhibit IL-5-mediated survival. These data demonstrate for the first time that the entire Ras-Raf-MEK-ERK pathway is critical in regulating eosinophil survival and that this may be in part due to the activation not only of Raf-1 but of ERK 1 and ERK 2.…”

Eosinophil-specific deletion of IκBα in mice reveals a critical role of NF-κB–induced Bcl-xL for inhibition of apoptosis

“…35,48 However, the PI3K and MAPK pathways were reported to play no major role for GM-CSF-mediated inhibition of apoptosis in human peripheral blood eosinophils and murine airway eosinophils. 49,50 In contrast, PI3K was involved in prevention of apoptosis in murine eosinophils isolated from the pleural cavity of allergic mice. 51 Similar effects were observed after engagement of b-adrenergic receptors on murine eosinophils, and this process appeared to be mediated by inhibition of the transcription factor forkhead in rhabdomyosarcoma.…”

Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line

“…Con¯icting results regarding the role of MEK/ MAPK in preventing apoptosis have emerged these last years (Kinoshita et al, 1995(Kinoshita et al, , 1997Miike et al, 1999;Scheid and Duronio, 1998). Recently, it has been shown that the MEK inhibitor PD98059 did not prevent the IL-3-or GM-CSF-mediated survival of MC/9 cells but reduced Bad phosphorylation (Scheid and Duronio, 1998).…”