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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.
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IMMUNOBIOLOGY
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 Kozutsumi, and
Toshiro Okazaki
From the Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; the Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; and the Department of Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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. (Blood. 2004;104:3285-3293)
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