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Interleukin-18 mRNA, but not interleukin-18 receptor mRNA, is constitutively expressed in islet b-cells and up-regulated by interferon-g. |
European Cytokine Network. Volume 11, Number 2, 193-205, June 2000, Articles originaux
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 Free Article
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Author(s) : T.-P. Hong, N. A Andersen, K. Nielsen, A. E Karlsen, G. Fantuzzi, D. L Eizirik, C. A Dinarello, T. Mandrup-Poulsen |
Summary : Interleukin-18 (IL-18) mRNA is expressed in islets of NOD mice during the early stages of insulitis and IL-18 has therefore been implicated as a contributing factor in immune-mediated beta-cell destruction. However, a recent study failed to show any effect of human IL-18 on the function of isolated rat islets. Since species differences have been shown between human and murine IL-18, the aims of this study were to investigate 1) if species homologous IL-18 alone or following IL-12 pre-exposure affected rat islet function, 2) if IL-18 dose-dependently modulated IL-1b or interferon-g (IFN-g) + tumor necrosis factor-a (TNF-a) actions on islet function, and 3) if IL-18 and IL-18 receptor (IL-18R) were expressed in rat islet beta-cells. Insulin release and nitric oxide (NO) production from isolated rat islets were measured after incubation with or without cytokines. RT-PCR was used to quantitate mRNA expression of IL-18 and the IL-18R signaling chain (IL-18Rb). There were no significant effects of 0.625-10 nM recombinant murine (rm) IL-18 alone on accumulated or glucose-challenged insulin release or NO production after 24 hours. Fifteen pg/ml of recombinant human (rh) IL-1b as well as 200 U/ml recombinant rat (rr) IFN-g + 250 U/ml rhTNF-a significantly increased islet NO production and inhibited both accumulated and glucose-challenged islet insulin release. However, rmIL-18 failed to modulate these effects of IL-1b or IFN-g + TNF-a. Although IL-12 induces IL-18R expression in Th1 and B lymphocytes, 24-hours rmIL-12 preincubation neither sensitized islets to effects of 10 nM of rm or rrIL-18 alone nor primed the islets to IL-1b actions on insulin release and NO production. IL-18Rb mRNA, which was expressed in human peripheral blood mononuclear cells (PBMC), was not expressed in rat insulinoma (RIN) cells or in isolated rat islets, even after exposure to IL-1b and/or IFN-g + TNF-a or IL-12. IL-18 mRNA was constitutively expressed in RIN cells, in FACS-purified rat beta-cells and in intact rat and mouse islets, and was up-regulated by IFN-g in an interferon regulatory factor-1- IRF-1) and NO – independent manner. However, IL-18 protein was undetectable in lysates and supernates of RIN cells by ECL, Western blotting and immunoprecipitation. In conclusion, we show for the first time that IL-18 but not IL-18R is expressed in rodent islet beta-cells. The physiological importance and pathological role of IL-18 originating from islet beta-cells deserve further investigation. |
Keywords : autoimmunity, insulin-dependent diabetes mellitus, interleukin-1, interleukin-12, nitric oxide, pancreatic islets. |
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