Vuoden 2012 konsepti .Polttavat jonisoivat UV-säteet ja reaktiiviset happiradikaalit ROS . Ceramidit ja S1P.

https://www.caymanchem.com/Article/2166

​Sphingosine-1-Phosphate vs. Ceramide: The Battle of the Burn​

2012-02-01

By Thomas G. Brock, Ph.D.

The luxurious warmth of the sun's rays on the face and shoulders slowly, subtly, gives way to redness and tenderness. Without attention, continued exposure produces a painful burn, followed days later by sloughing of a layer of dead skin tissue. This familiar experience is one demonstration of the ability of ionizing radiation, in the form of ultraviolet light from the sun, to generate reactive oxygen species (ROS) that trigger the release of ceramide within cells, leading to cell death. Remarkably, the effects of ceramide can be diminished by its related metabolite, sphingosine 1-phosphate (S1P). This article introduces these lipids and their complex interrelationship.

Ceramide Metabolism

Sphingolipids are, like phospholipids, integral components of biological membranes. Ceramide, the simplest of the sphingolipids, is composed of a sphingosine base and an amide-linked acyl chain of variable length. Ceramide can be synthesized de novo in the endoplasmic reticulum through the serine palmitoyl transferase pathway, which involves the production of the intermediate sphinganine and its conversion to the immediate precursor dihydroceramide by ceramide synthases, CerS (Figure 1). Interestingly, CerS was initially identified in yeast as the longevity assurance gene 1 (LAG1), because deletion of LAG1 prolongs the replicative lifespan of Saccharomyces cerevisiae. The mouse homolog of LAG1 is called longevity assurance homolog 1 (LASS1) or upstream of growth and differentiation factor 1 (UOG1). LASS1 activity, which specifically regulates the synthesis of C18-ceramide, determines cell longevity rather than mouse aging, since reduced activity is associated with a proliferative, cancerous phenotype.<sup>1

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Sphingosine 1-Phosphate Effects

S1P was first thought to have its effects intracellularly, acting as a second messenger, interacting with and modulating the activities of specific target proteins. While this certainly happens,10 most current research focuses on the signaling of S1P as a secreted ligand, activating G-protein coupled receptors in an autocrine or paracrine fashion. These receptors were initially identified as EDG (endothelial differentiation gene) receptors and were orphan receptors. With the identification of S1P as a ligand for five of the EDG receptors, these have been renamed: S1P₁ (EDG1), S1P₂ (EDG5), S1P₃ (EDG3), S1P₄ (EDG6), and S1P₅ (EDG8). S1P₁ and S1P₃ were first isolated from endothelial cells, while S1P₂ was first found on rat brain and vascular smooth muscle cells, S1P₄ was found on dendritic cells and S1P₅ on rat PC12 (prostate cancer) cells. The five S1P receptors share high sequence identity with the cannabinoid and lysophosphatidic receptors, which are also G-protein coupled receptors for lipid ligands. Through these receptors, S1P regulates cell proliferation, differentiation, stress fiber formation, cell motility and migration, and cell survival.¹¹

Perhaps one of the most exciting effects of S1P relates to its action on lymphocyte trafficking. The concentration of S1P in lymphoid tissues is normally low compared with that of the lymph. Lymphocytes within lymphoid tissues respond to this gradient, through the S1P₁ receptor, by migrating from the tissue into the lymph. If the S1P levels within lymphoid nodes are elevated, by inhibition of S1P lyase, inflammation, or by the addition of stable S1P analogs, then lymphocyte egress is blocked. This greatly reduces the number of circulating lymphocytes and diminishes their ability to participate in the immune response. S1P analogs include SEW2871 , FTY720 , and (S)-FTY720-phosphonate. Because of its ability to reduce lymphocytic trafficking, FTY720 is effective in the treatment of multiple sclerosis.

S1P vs. Ceramide

Since ceramide is readily converted to sphingosine, which in turn can give rise to the potent mediator S1P, one might ask if S1P mediates any of the pro-apoptotic actions of ceramide. In fact, ionizing radiation initially downregulates sphingosine kinase 1, impairing the production of S1P.¹² Moreover, added S1P has been shown to be a radioprotectant, preventing oocyte apoptosis and male sterility in irradiated mice.^13-15 Isolated, proliferating endothelial cells, when irradiated, undergo an early premitotic apoptosis that is dependent on ceramide production in many cells, followed by a delayed death resulting from DNA damage in other cells. S1P protects cells from ceramide-dependent apoptosis but not from DNA damage-induced mitotic death.¹⁶ Also, mice maintained on S1P analogs are significantly protected against radiation-induced lung injury.¹⁷ It should be noted that these effects are seen over a 6 week period and appear to rely on altered gene expression in response to S1P analogs. Signaling via S1P₁, S1P₂, and S1P₃, the analogs decrease vascular leak through several effects on the cytoskeletal and adhesive properties of endothelial cells.¹⁷ In addition, over this prolonged period, radiation increases the expression of both sphingosine kinase isoforms, perhaps suggesting the existence of a delayed protective feedback loop. Taken together, these studies suggest that intervention through S1P is an attractive approach to ameliorating the ceramide-dependent effects of ionizing radiation.