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

Abstract

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)

Sphingomyelin Synthase 1-generated Sphingomyelin Plays an Important Role in Transferrin Trafficking and Cell Proliferation

“…We previously reported on the biological role of SMS, which is one of most important enzymes regulating hematopoietic cell proliferation, differentiation, and death through "SM cycle" (21,(45)(46)(47). Up-regulation of SMS promotes cell proliferation in lymphocytes, hepatocytes, astrocytes, and fibroblasts (48 -50).…”

Human γδ T lymphocytes induce robust NK cell–mediated antitumor cytotoxicity through CD137 engagement

“…Usually NK cells do not survive for a long period of time without cytokine support. 21 Therefore, to understand the mechanisms of ␥␦ T lymphocyte-mediated NK-cell activation in a more physiologic model, in this study we used a short-term culture of fresh NK cells purified from PBMCs of healthy donors and ␥␦ T lymphocytes expanded in vitro. As shown in Figure 1A, fresh NK cells cultured with media or ␥␦ T lymphocytes alone do not express CD69, a molecule associated with NK-cell activation.…”

Cloning, characterization, expression and comparative analysis of pig Golgi membrane sphingomyelin synthase 1

“…Thus, DAG, an important signalling molecule for cell growth through protein kinase C activation (Hampton and Morand, 1989) acts competitively against ceramide-induced apoptosis (Hannun and Bell, 1989). Activation of SMS prevents apoptosis either by using ceramide as a substrate or by increasing the levels of DAG (Hannun and Luberto, 2004;Taguchi et al, 2004;Albi et al, 2005). In this regard, after thioacetamide-induced injury, the SM/PC ratio significantly increased in microsomal fraction from liver, suggesting the involvement of SMS in tissue recovery (Miro-Obradors et al, 1993).…”

“…In this regard, after thioacetamide-induced injury, the SM/PC ratio significantly increased in microsomal fraction from liver, suggesting the involvement of SMS in tissue recovery (Miro-Obradors et al, 1993). SMS was also found activated in IL-2-induced proliferation of natural killer cells (Taguchi et al, 2004) and in chemotherapy-resistant blast cells obtained from refractory leukemia patients (Itoh et al, 2003). Conversely, inhibition of SMS contributed to D609-induced tumor cell death via modulation of the cellular levels of ceramide and DAG (Meng et al, 2004) and to Fas-induced T cell apoptosis (Watanabe et al, 2004).…”