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Sphingosine 1-Phosphate Affects Cytokine-Induced Apoptosis in Rat Pancreatic Islet ß-Cells

Departments of Pharmacology and Toxicology (S.G.L., S.M.S., M.-H.L.) and Pediatrics (L.D.M.), School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, New York 14214

Address all correspondence and requests for reprints to: Suzanne G. Laychock, Ph.D., 102 Farber Hall, Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, The University at Buffalo, Buffalo, New York 14214. E-mail: laychock{at}buffalo.edu.

Cytokines mediate pancreatic islet ß-cell apoptosis and necrosis, leading to loss of insulin secretory capacity and type 1 diabetes mellitus. The cytokines, IL-1ß and interferon-, induced terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining of rat islet cells within 48 h by about 25–30%, indicative of apoptosis and/or necrosis. Sphingosine 1-phosphate (S1P) at nanomolar concentrations significantly reduced islet cell cytokine-induced TUNEL staining. Similar effects were observed in INS-1 cells. The dihydro analog of S1P also reduced the percentage of TUNEL stained islet and INS-1 cells, whereas the S1P receptor antagonist BML-241 blocked the protective effects. Pertussis toxin did not affect the S1P protective response. In the presence of a phospholipase C antagonist, U73122, there was significant inhibition of the S1P protective effects against apoptosis/necrosis. S1P stimulated INS-1 cell protein kinase C activity. Carbamylcholine chloride acting through muscarinic receptors also inhibited cytokine-induced TUNEL staining in pancreatic islet cells. S1P and/or dihydro-S1P also antagonized cytokine-induced increases in cytochrome c release from mitochondria and caspase-3 activity in INS-1 cells, which are indicative of cell apoptosis vs. necrosis. S1P failed to affect nitric oxide synthase activity after 48 h. Thus, the evidence suggests that S1P acting on S1P receptors coupled to G_q mediates protective effects on islet ß-cells against cytokine-induced apoptosis.

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