Activation of the Sphingomyelin Signaling Pathway in Intact EL4 Cells and in a Cell-Free System By IL-1β

Mathias, Shalini; Younes, Anas; Kan, Chu-Cheng; Orlow, Irene; Joseph, Cecil K.; Kolesnick, Richard

doi:10.1126/science.8424175

Cited by 422 publications

(232 citation statements)

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“…To determine exogenous stimulation of sphingomyelin hydrolysis by ligand-induced receptor activation, LNCaP cells were exposed to IL-1b, a well known activator of the sphingomyelin pathway in other cellular systems (Kolesnick & Golde, 1994;Mathias et al, 1993;Santana et al, 1996). A 30 min treatment with 1 ng ml 71 IL1-b produced a marked reduction of sphingomyelin levels paralleled by enhanced formation of ceramide (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Distinct effects of ceramide‐generating pathways in prostate adenocarcinoma cells

Condorelli

Canonico

Sortino

1999

British J Pharmacology

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1 Ceramide, generated by the hydrolysis of sphingomyelin, mediates the actions of several cytokines such as tumour necrosis factor-a (TNF-a) interferon-g and interleukin-1b (IL-1b), including their inhibitory e ect on tumour proliferation. We have evaluated the role of ceramide in the proliferation of prostate cancer by using the human prostate adenocarcinoma LNCaP cell line. 2 Treatment of LNCaP cells with neutral or acidic sphingomyelinase or addition of C8-or C2-ceramide, two cell permeable analogues of endogenous ceramide, induced a profound inhibition of cell proliferation. This e ect appeared after 24 h, was still present after 72 h of exposure to the drugs and exhibited concentration-dependency (10 ± 200 and 5 ± 200 mU ml 71 for neutral and acidic sphingomyelinase, respectively, and 1 ± 25 mM for C8-ceramide). 3 The inhibitory e ect on cell growth caused by neutral sphingomyelinase and ceramides was rapidly reversible as LNCaP cells rapidly regained their previous proliferation rate following withdrawal of the treatment. 4 IL-1b produced profound inhibition of LNCaP cell proliferation and caused enhanced ceramide formation. 5 No clear features of apoptotic cell death were detectable by either oligonucleosome formation, cyto¯uorimetric analysis or nuclear staining following exposure of LNCaP cells to neutral sphingomyelinase, ceramide or IL-1b. However, clear changes in LNCaP cell cycle distribution were detectable following these treatments. In contrast, treatment with acidic sphingomyelinase or TNF-a induced apoptotic death detectable by¯ow cytometric analysis and bisbenzimide staining. 6 In conclusion, our data demonstrate that preferential activation of distinct enzymatic pathways by cytokines may lead to di erent outcomes in the viability of LNCaP cells.

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Section: Resultsmentioning

confidence: 99%

Distinct effects of ceramide‐generating pathways in prostate adenocarcinoma cells

Condorelli

Canonico

Sortino

1999

British J Pharmacology

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“…Three forms of SMases are candidates for SM hydrolysis. Acid SMase (pH optimum 4.5 ± 5.0) has been associated in apoptosis signaling triggered by TNFa (Wiegmann et al, 1994), antiFas (Cifone et al, 1994), and anti-CD28 (Boucher et al, 1995); activation of a membrane bound neutral SMase (pH optimum 7.4) has also been described with TNFa (Wiegmann et al, 1994), anti-Fas antibody (Tepper et al, 1995), IL-1b (Mathias et al, 1993) and daunorubicin ; finally, a cytosolic neutral SMase has been implicated in vitamin D3 induced differentiation (Okazaki et al, 1994). A recent study by Kolesnick's group clearly demonstrated that acid SMase-deficient human lymphoblasts as well as lung endothelium, thymus and spleen of acid SMase knockout mice are defective in IRinduced apoptosis (Santana et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation

et al. 1998

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The mechanism(s) by which ionizing radiation (IR) induces cell death is of fundamental importance in understanding cell sensitivity and resistance. Here we evaluated the response to IR of two subclones of the autonomous human erythromyeloblastic cell line TF-1: TF-1-34 (which expresses CD34) and TF-1-33 (which lacks CD34). In clonogenic assays, TF-1-34 cells were found to be relatively less sensitive to IR compared to TF-1-33 cells based on the D 0 determination (3.01 vs 1.56 Gy). Furthermore, after IR at 12 Gy, TF-1-33 cell viability decreased by *50% within 24 h, whereas TF-1-34 cell growth was unaffected during this time. Gradual loss of TF-1-34 cell viability was observed only after 48 h. Morphological and molecular analysis revealed that TF-1-33 cells died of apoptosis, and TF-1-34 cells of delayed reproductive cell death. While IR produced comparable amounts of DNA double strand breaks (DSB) in both cell lines, TF-1-34 retained DSB much longer than TF-1-33 suggesting that radioresistance and the defective apoptotic response of TF-1-34 cells was not related to a higher DNA repair capacity. However, the lack of an apoptotic response in TF-1-34 was correlated to the absence of a sphingomyelin (SM)-ceramide (CER) signaling pathway. Indeed, IR triggered in TF-1-33 cells but not in TF-1-34, SM hydrolysis (25% at 12 Gy) and CER generation (450%) through the activation of neutral but not acid sphingomyelinase. Synthetic cell permeate CER induced apoptosis in both TF-1-33 and TF-1-34 cells. This study indicates that alterations of the SM-CER signaling pathway can significantly influence the cell death process as well as the survival of acute myeloid leukemia cells after IR exposure.

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“…indeed several mediators known to increase the intracellular levels of ceramide are involved in the early immune response, i.e., TCR triggering, IL-1␤, TNF-␣, IFN-␥, and CD28 ligation (10,(12)(13)(14)(15)(32)(33)(34). When the T cell forms Ag-specific conjugates with APC, a supramolecular activation cluster is observed at the T-APC contact zone.…”

Section: Discussionmentioning

confidence: 99%

Ceramide-Induced TCR Up-Regulation

Menné

Lauritsen

Dietrich

et al. 2000

The Journal of Immunology

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The TCR is a constitutively recycling receptor meaning that a constant fraction of TCR from the plasma membrane is transported inside the cell at the same time as a constant fraction of TCR from the intracellular pool is transported to the plasma membrane. TCR recycling is affected by protein kinase C activity. Thus, an increase in protein kinase C activity affects TCR recycling kinetics leading to a new TCR equilibrium with a reduced level of TCR expressed at the T cell surface. Down-regulation of TCR expression compromises T cell activation. Conversely, TCR up-regulation is expected to increase T cell responsiveness. The purpose of this study was to identify and characterize potential pathways for TCR up-regulation. We found that ceramide affected TCR recycling dynamics and induced TCR up-regulation in a concentration- and time-dependent manner. Experiments applying phosphatase inhibitors indicated that ceramide-induced TCR up-regulation was most probably mediated by serine/threonine protein phosphatase 2A. Analyses of T cell variants demonstrated that TCR up-regulation was dependent on the presence of an intact CD3γ L-based motif and thus acted on TCR engaged in the recycling pathway. Finally, we showed that TCR up-regulation probably plays a physiological role by increasing T cell responsiveness. Thus, by affecting the TCR recycling kinetics, T cells have the potential both to up- and down-regulate TCR expression and thereby adjust T cell responsiveness.

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Activation of the Sphingomyelin Signaling Pathway in Intact EL4 Cells and in a Cell-Free System By IL-1β

Cited by 422 publications

References 50 publications

Distinct effects of ceramide‐generating pathways in prostate adenocarcinoma cells

Distinct effects of ceramide‐generating pathways in prostate adenocarcinoma cells

Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation

Ceramide-Induced TCR Up-Regulation

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