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-induced survival of natural killer (NK) cells involving phosphatidylinositol-3 kinase-dependent reduction of ceramide through acid sphingomyelinase, sphingomyelin synthase, and glucosylceramide synthase
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DOI：
10.1182/blood-2004-03-0900
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发表时间：
2004-11-15
期刊：
影响因子：
20.3
通讯作者：
Okazaki, T
中科院分区：
文献类型：
--
作者：
Taguchi, Y;Kondo, T;Okazaki, T
白细胞介素2（IL-2）通过减少神经酰胺沿着使人自然杀伤（NK）细胞KHYG-1免于凋亡。相反，神经酰胺的增加抑制IL-2挽救的存活。通过补充IL-2使IL-2剥夺诱导的酸性鞘磷脂酶（SMase）活化以及葡萄糖神经酰胺合酶（GCS）和鞘磷脂合酶（SMS）抑制正常化。磷脂酰肌醇-3（PI-3）激酶抑制剂或LY 294002抑制IL-2拯救的存活，但促分裂原活化蛋白激酶抑制剂PD 98059和Janus酪氨酸激酶/sIgnal转导子和转录激活子途径抑制剂AG 490则不抑制IL-2拯救的存活。LY 294002通过激活酸性SMase和抑制GCS和SMS抑制IL-2诱导的神经酰胺减少，表明PI-3激酶通过酶调节积极参与神经酰胺减少。事实上，组成型活性PI-3激酶通过抑制酸性SMase和激活GCS和SMS来增强生长速率和神经酰胺减少。此外，LY 294002抑制IL-2诱导的转录水平以及酸性SMase和GCS的mRNA和蛋白质水平的变化，但不影响mRNA的稳定性。这些结果表明，通过调节酸性SMase、GCS和SMS的PI-3激酶依赖性神经酰胺减少在IL-2挽救的存活中起作用。NK细胞。(C)2004年，美国血液学会。
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 inhibit or, 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. (C) 2004 by The American Society of Hematology.