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Gene Expression Unit (M.-C.C., V.P.-E., D.L.E.), Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium; and Department of Medical Cell Biology (N.W., D.L.E.), Uppsala University, S-751 23 Uppsala, Sweden
Address all correspondence and requests for reprints to: D. L. Eizirik, Gene Expression Unit, Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090, Brussels, Belgium. E-mail: deizirik{at}mebo.vub.ac.be
The cytokine interleukin (IL)-1ß induces a biphasic effect in rat pancreatic islets, with an early and transitory stimulation of insulin release followed by progressive functional suppression. To clarify the mechanisms involved in these effects, we have recently performed a differential display of messenger RNA (mRNA) by RT-PCR (DDRT-PCR) on rat ß-cells exposed for 6 or 24 h to IL-1ß. Among the different IL-1ß-induced genes, there was an early and transient increase in phospholipase D-1 (PLD1) expression. PLD1 can induce phosphatidic acid formation and subsequent activation of protein kinase C, a process which stimulates insulin release. In the present study, we characterized the regulation of PLD isoforms by IL-1ß in pancreatic ß-cells. By using different combinations of primers and RT-PCR, we observed that IL-1ß induces an early increase (2 and 6 h) in the expression of both alternatively spliced isoforms of PLD1 (PLD1a and 1b). Prolonged exposure to IL-1ß (12 and 24 h) caused a decrease of PLD1a mRNA expression compared with control ß-cells, and lead to a return of PLD1b mRNA to basal level. NG-methyl-L-arginine (L-MA), a blocker of the inducible form of nitric oxide synthase (iNOS), prevented this late inhibitory effect of IL-1ß, suggesting that IL-1ß-induced decrease in PLD1a expression is NO-mediated. IL-1ß induced an early (2–6 h) and sustained (16–24 h) increase in PLD1a mRNA expression in insulin-producing RINm5F cells. This was paralleled by a cytokine-induced increase in PLD1 protein expression and enzyme activity. RINm5F cells, but not primary ß-cells, expressed PLD2, and the expression of this gene was not affected by IL-1ß. In conclusion, we have shown that the cytokine IL-1ß regulates PLD1 expression in primary and clonal ß-cells. The early induction of PLD1 probably contributes to the early stimulatory effects of IL-1ß on islet insulin release.
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