Interleukin-2-induced survival of natural killer (NK) cells involving phosphatidylinositol-3 kinase-dependent reduction of ceramide through acid sphingomyelinase, sphingomyelin synthase, and glucosylceramide synthase.
Interleukin 2 (IL-2) rescued human natural killer (NK) KHYG-1 cells from apoptosis along with a reduction of ceramide. Conversely, an increase of ceramide inhibited IL-2-rescued survival. IL-2 deprivation-induced activation of acid sphingomyelinase (SMase) and inhibition of glucosylceramide synthase (GCS) and sphingomyelin synthase (SMS) were normalized by IL-2 supplementation. A phosphatidyl inositol-3 (PI-3) kinase inhibitor, LY294002, inhibited IL-2-rescued survival, but a mitogen-activated protein kinase inhibitor, PD98059, and an inhibitor of Janus tyrosine kinase/signal transducer and activator of transcription pathway, AG490, did not. LY294002 inhibited IL-2-induced reduction of ceramide through activation of acid SMase and inhibition of GCS and SMS, suggesting the positive involvement of PI-3 kinase in ceramide reduction through enzymatic regulation. Indeed, a constitutively active PI-3 kinase enhanced growth rate and ceramide reduction through inhibition of acid SMase and activation of GCS and SMS. Further, LY294002 inhibited IL-2-induced changes of transcriptional level as well as mRNA and protein levels in acid SMase and GCS but did not affect the stability of the mRNAs. These results suggest that PI-3 kinase-dependent reduction of ceramide through regulation of acid SMase, GCS, and SMS plays a role in IL-2-rescued survival of NK cells.
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Syogoin-Kawaramachi, Sakyo-ku, Kyoto 606-8507, Japan.
Yoshimitsu
Y
Taguchi
Tadakazu
T
Kondo
Mitsumasa
M
Watanabe
Michihiko
M
Miyaji
Hisanori
H
Umehara
Yasunori
Y
Kozutsumi
Toshiro
T
Okazaki
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000201:enzymology*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D000970:Antineoplastic Agents; D002518:Ceramides; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005964:Glucosyltransferases; D007376:Interleukin-2; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D013108:Sphingomyelin Phosphodiesterase; D017855:Transferases (Other Substituted Phosphate Groups); D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C023246:ceramide glucosyltransferase; C070186:phosphatidylcholine-ceramide phosphocholine transferase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one