Recent advances in the immunobiology of ceramide

Abstract

Ceramide, a sphingosine-based lipid molecule, has emerged as a key regulator of a wide spectrum of biological processes such as cellular differentiation, proliferation, apoptosis and senescence. Sphingomyelinase-dependent hydrolysis of sphingomyelin, and de novo synthesis involving the coordinated action of serinepalmitoyl transferase and ceramide synthase, are the two major pathways involved in ceramide synthesis. Clustering of plasma membrane rafts into ceramide enriched platforms serves as an important transmembrane signaling mechanism for cell surface receptors. Ceramides have been implicated in apoptosis, stress-signaling cascades as well as ion channels. There is accumulating evidence that targeted manipulation of ceramide metabolism pathway has immense therapeutic potential and may eventually prove to be a boon in the design of novel strategies and development of innovative treatments for diverse conditions including cardiovascular diseases, cancer and Alzheimer's disease. As yet uncharacterized natural ceramide analogs and novel inhibitors of ceramide metabolism might prove to be potent drugs. In this review, we discuss significant advances that continue to provide intriguing insights into the complex cellular and molecular mechanisms underlying ceramide-mediated signaling cascades.

Short-term magnesium deficiency upregulates sphingomyelin synthase and p53 in cardiovascular tissues and cells: relevance to the de novo synthesis of ceramide

“…We (48) have previously noted, using primary cerebral and peripheral vascular muscle cells in culture, that a variation in extracellular Mg 2ϩ concentration ([Mg 2ϩ ] o ) influences the cellular levels of SM, PC, DAG, and ceramide. Ceramide, either released as a consequence of SMase acting on SM or activation of SPT, CS, or activation of SMS, is now thought to play important roles in fundamental processes such as cell proliferation, membranereceptor functions, angiogenesis, microcirculatory functions, immune inflammatory responses, cell adhesion, atherogenesis, senescence, and programmed cell death (8,16,17,19,28,29,34,51,67,72,73). Although the activation of SMase, SPT-1, and SPT-2 (the rate-limiting enzymes for the biosynthesis of ceramide) by low [Mg 2ϩ ] o results in (and ensures) ceramide production in cardiovascular tissues (10,11), the activation of CS and/or SMS by low [Mg 2ϩ ] o result in additional levels of ceramide.…”

Short-term magnesium deficiency upregulates ceramide synthase in cardiovascular tissues and cells: cross-talk among cytokines, Mg2+, NF-κB, and de novo ceramide

“…It is now, generally, accepted that ceramides can be produced in many types of cells and tissues when they are exposed to ultraviolet radiation, endotoxins, retinoic acid, ionizing radiation, balloon injury of arterial vessels, phorbol esters, serum deprivation, daunorubicin, apoptotic signals, as well as cytokines, among other agents (21,24,33,36,44,59,73). Many of these agents, including cytokines, are known to activate SPT, SMS, SMases, and CS to produce ceramides in many cell types (31,69,71).…”

“…Three of us (55) have previously noted, using primary cerebral and peripheral VSMCs in culture, that a variation in [Mg 2ϩ ] o influences the cellular levels of SM, PC, DAG, and ceramide. Ceramide, either released as a consequence of SMase acting on SM and/or activation of either SPT or SMS or activation of CS, is now thought to play important roles in fundamental pathophysiologic processes such as cell proliferation, membrane receptor functions, angiogenesis, microcirculatory functions, immune inflammatory responses, cell adhesion, atherogenesis, senescence, programmed cell death (12,21,22,24,31,33,36,44,58,59,73,79,82,83), as well as cellular membrane transport and distribution of Mg 2ϩ in VSMCs (82). Although the activation of N-SMase, SPT-1, and SPT-2 as well as SMS by low [Mg 2ϩ ] o results in (and ensures) ceramide production in cardiovascular tissues (14 -16), the activation of CS by low [Mg 2ϩ ] o could result in additional levels of de novo ceramide.…”

“…Although cytokine secretion has been, and is, a widely studied process, specific mechanisms for regulation of cytokine (and chemokine) release still remain to be determined (37,71). Interestingly, cytokines have recently been implicated in the generation/release of ceramide (32,59) as well as the activation of SMases (41,59). We hypothesized that 1) de novo generation of ceramide in short-term MgD (14) would upregulate and release several cytokines and chemokines into sera of such animals and in primary cultured VSMCs; 2) imbibing low levels of a water-soluble Mg salt in drinking water would inhibit or reverse the predicted effects of dietary deficiency of Mg on the upregulation and release of the cytokines and chemokines; 3) blockage of de novo synthesis (with a specific inhibitor of CS) in primary cultured VSMCs would result in an attenuation of the generation of select cytokines/chemokines in these vascular cells; and 4) blockage of low [Mg 2ϩ ] o -induced activation of N-SMase would result in reduced levels of ceramide and an attenuation of the generation of select cytokines/chemokines.…”

Anti–Dengue Virus Nonstructural Protein 1 Antibodies Cause NO-Mediated Endothelial Cell Apoptosis via Ceramide-Regulated Glycogen Synthase Kinase-3β and NF-κB Activation

“…The formation of lipid rafts, the membrane microdomains that are enriched in cholesterol and glycosphingolipids, play an important role in cellular signaling in response to various stimuli (31)(32)(33)(34)(35). Ceramide, which is enriched in lipid rafts, acts as a second messenger of multiple extracellular stimuli in cell survival, inflammation, and apoptotic cell death (36)(37)(38)(39)(40)(41). We investigated the formation of raft structure and the generation of cellular ceramide after binding of anti-DENV NS1 Abs to endothelial cells.…”