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Blood, 15 November 2004, Vol. 104, No. 10, pp. 3285-3293. Prepublished online as a Blood First Edition Paper on July 22, 2004; DOI 10.1182/blood-2004-03-0900. This Article Full Text (PDF) All Versions of this Article: 2004-03-0900v1 104/10/3285    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Taguchi, Y. Articles by Okazaki, T. Search for Related Content PubMed PubMed Citation Articles by Taguchi, Y. Articles by Okazaki, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 25, 2004 Accepted June 28, 2004 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 Yoshimitsu Taguchi, Tadakazu Kondo, Mitsumasa Watanabe, Michihiko Miyaji, Hisanori Umehara, Yasunori Kotutumi, and Toshiro Okazaki* Department of Laboratory of Membrane biochemistry and biophysics, Kyoto University, Graduate School of Biostudies, Kyoto, Japan Department of Hematology/Oncology, Kyoto University, Gradyate School of Medicine, Kyoto, Japan Department of Clinical Immunology, Kyoto University, Graduate School of Medicine, Kyoto, Japan * Corresponding author; email: toshiroo{at}kuhp.kyoto-u.ac.jp. IL-2 rescued human natural killer (NK) KHYG-1cells 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 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 play a role in IL-2-rescued survival of NK cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z.-X. Jin, C.-R. Huang, L. Dong, S. Goda, T. Kawanami, T. Sawaki, T. Sakai, X.-P. Tong, Y. Masaki, T. Fukushima, et al. Impaired TCR signaling through dysfunction of lipid rafts in sphingomyelin synthase 1 (SMS1)-knockdown T cells Int. Immunol., November 1, 2008; 20(11): 1427 - 1437. [Abstract] [Full Text] [PDF] H.-F. Bao, Z.-R. Zhang, Y.-Y. Liang, J. J. Ma, D. C. Eaton, and H.-P. Ma Ceramide mediates inhibition of the renal epithelial sodium channel by tumor necrosis factor-{alpha} through protein kinase C Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1178 - F1186. [Abstract] [Full Text] [PDF]

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