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Sphingosine Kinase Activity and Sphingosine-1 Phosphate Production in Rat Pancreatic Islets and INS-1 Cells

Response to Cytokines

¹ Department of Pharmacology and Toxicology, The State University of New York, Buffalo, New York
² Department of Pediatrics, School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, New York

Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid with the potential to mobilize Ca²⁺, to inhibit apoptosis, and to promote mitogenesis. Sphingosine kinase (SPHK) and S1P were characterized in INS-1 insulinoma cells and isolated rat islets of Langerhans. SPHK activity increased in INS-1 cell homogenates treated with interleukin-1ß (IL-1ß) or tumor necrosis factor- (TNF-), and responses were additive. IL-1ß or TNF- increased islet SPHK activity within 15 min to 1 h; activity remained elevated after 8 h. SPHK2 was the predominant active isoform in INS-1 cells; little or no SPHK1 activity was detected. Cytokines increased endogenous S1P biosynthesis in ³²P_i-prelabeled INS-1 cells, and cycloheximide inhibited the response after 8 h, suggesting that protein synthesis mediated the response. There was no [³²P]S1P release from cells. Compared with basal values, IL-1ß and TNF- induced increases in SPHK1a mRNA levels relative to 18S ribosomal RNA in INS-1 cells within 1 h; relative SPHK2 mRNA levels were unchanged after cytokine treatment. IL-1ß, but not TNF-, induced relative SPHK1a mRNA expression levels within 1 h in islets, whereas SPHK2 mRNA levels were unchanged. Thus, IL-1ß and TNF- induced an early and sustained increase in SPHK activity in INS-1 cells and isolated islets, suggesting that S1P plays a role in the pathological response of pancreatic ß-cells to cytokines.

Abbreviations: EDG, endothelial differentiation gene–encoded receptor; FAF-BSA, fatty acid–free BSA; FBS, fetal bovine serum; IL-1ß, interleukin-1ß; PKC, protein kinase C; S1P, sphingosine-1 phosphate; SPHK sphingosine kinase; TLC, thin-layer chromatography; TNF-, tumor necrosis factor-

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