Activation of PI3K-Akt pathway mediates antiapoptotic effects of beta-adrenergic agonist in airway eosinophils.
beta-Adrenoceptor agonists reportedly decrease spontaneous apoptosis of peripheral blood eosinophils; however, its signaling pathway is unknown. Survival signals can be elicited by the activation of phosphatidylinositol 3-kinase (PI3K) and Akt, both of which are known to be potent regulators of apoptosis, and Akt in turn inactivates Forkhead transcription factors, including FKHR (Forkhead in rhabdomyosarcoma). We have investigated the effect of beta-agonists on apoptosis of local eosinophils isolated from the airways and the involvement of PI3K, Akt, and FKHR in its survival signal. Eosinophils obtained from immunized mice by bronchoalveolar lavage after allergen provocation underwent apoptosis in a time-dependent manner. Incubation of eosinophils with isoproterenol or formoterol dose-dependently inhibited both spontaneous eosinophil apoptosis and apoptosis induced by Fas receptor activation. Incubation with cAMP or forskolin also inhibited eosinophil apoptosis. The PI3K inhibitors wortmannin and LY-294002 and an Akt inhibitor, 1-L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, but not a mitogen-activated protein kinase kinase inhibitor PD-98059, blocked isoproterenol-mediated eosinophil survival. Wortmannin also inhibited cAMP-mediated eosinophil survival. Isoproterenol rapidly induced phosphorylation of Akt and FKHR in eosinophils in a PI3K-dependent manner. These findings indicate that the PI3K-Akt-FKHR pathway conveys a critical survival signal induced by beta-agonists in airway eosinophils.
Machida
Kentaro
K
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Inoue
Hiromasa
H
Matsumoto
Koichiro
K
Tsuda
Miyuki
M
Fukuyama
Satoru
S
Koto
Hiroshi
H
Aizawa
Hisamichi
H
Kureishi
Yasuko
Y
Hara
Nobuyuki
N
Nakanishi
Yoichi
Y
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects* / Q000201:enzymology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007545:Isoproterenol / Q000494:pharmacology*; D008168:Lung / Q000201:enzymology / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000242:Cyclic AMP; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007545:Isoproterenol; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D019014:fas Receptor; C467200:Foxo1 protein, mouse