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  • Whitley Vistisen posted an update 3 months, 2 weeks ago

    The capacity of ceramide to promote apoptosis is limited by lysophosphatidate, both of which represent lipid messengers that underwrite proliferative signaling in many cell lines.The downstream systems mediating these antiapoptotic responses are presently uncertain, but may entail downstream. Ceramidemediated apoptosis is subject to reciprocal modulation by diglyceride and sphingosine in HL and U human leukemia cells.Under physiological conditions, chronic elevation of diglyceride promotes differentiation along a monocytic Targetmol’s Magnesium glycinate lineage in myeloid cells. Interestingly, the lethal actions of ceramide are attenuated or abolished acutely by endogenous and exogenous diglycerides without any evidence of the initiation of a differentiation program. Qualitatively similar cytoprotective inuences are associated with pharmacological PKC activators, including both stage and stage tumorpromoting phorboids. Conversely, ceramiderelated cytotoxicity is sharply potentiated by sphingoid bases at sublethal concentrations. Comparable augmentation of the ceramide response is produced by sphingosine and sphinganine; moreover, the potentiative capacity of sphingosine is evenly associated with both and forms of er ythro sphingosine and threo sphingosine.Ceramide action is also enhanced by highly selective pharmacological inhibitors of PKC at sublethal concentrations.The idea that acute inhibition of PKC constitutes a proapoptotic signal strongly supports the participation of sphingoid bases and other lysosphingolipids as biologically relevant effectors in the apoptotic component of cell survival.In contrast to TNF and IL, LPS does not cause sphingomyelin hydrolysis and thus stimulates KSRCAPK without generation of ceramide.Strong structural similarity between ceramide and lipid A. Thus, LPS provokes cellular responses by mimicking the second messenger function of ceramide.Dolichylphosphateinduced apoptosis is associated with activation of MAP kinase, and inhibition of tyrosine phosphorylation of MAPK by herbimycin A results in inhibition of DNA fragmentation inhibits apoptosis in macrophages.These investigators have also found that exogenous addition of arachidonic acid induces sphingomyelin hydrolysis and reproduces effects of ceramide on cell growth.Acute addition of synthetic diacylglycerol, a candidate mediator of TNF responses, is without effect on either sphingomyelin turnover or cell growth.Given that the TNF activates the sphingomyelin pathway, resulting in the generation of ceramide by stimulation of neutral sphingomyelinase, arachidonic acid has been suggested to serve as a mediator of the TNF effects on sphingomyelin turnover.In HL cells, TNF reportedly stimulates a rapid release of arachidonic acid; in turn, arachidonic acid stimulates sphingomyelin hydrolysis through the activation of phospholipase A and concomitant ceramide generation.This effect can be mimicked by oleate; the methyl ester and alcohol derivatives of fatty acids are inactive. Etherlinked glycerophospholipids such as octadecylmethylrac glycerophosphocholine induce apoptosis in human leukemic HL cells. Lipid hydroperoxides such as hydroperoxy eicosatetraenoic acid induce cell death in E cells, a chronically human immunodeciency virus. The effect is apparently due to a marked reduction of glutathione peroxidase activity.This suggests that the effect of these lipids can contribute to the depletion of CD T cells that occurs in AIDS.Inhibition of this kinase after metabolic degradation of ether lipids by phospholipase D may contribute to the cytotoxicity. The biological actions of these lipids are thought to be mediated in part through tyrosine kinases associated with growth factor receptors. CD B lymphocytes present a morphology similar to that of cells undergoing programmed cell death.