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Fas Ligand Down-Regulates Cytokine-Induced Fas Receptor Expression on Insulinoma (NIT-1), But Not Islet Cells, from Autoimmune Nonobese Diabetic Mice

Institute of Diabetes Gerhardt Katsch Karlsburg e. V. (P.A., P.H., E.S., S.B., C.S.), 17495 Karlsburg, Germany; Department of Physiology, Ernst Moritz Arndt University (R.R.), 17489 Greifswald, Germany; and Walter and Eliza Hall Institute of Medical Research (L.C.H.), Parkville 3050, Australia

Address all correspondence and requests for reprints to: Petra Augstein, Ph.D., Institute of Diabetes Gerhardt Katsch Karlsburg e.V, Greifswalder Strasse 11e, 17495 Karlsburg, Germany. E-mail: augstein{at}mail.uni-greifswald.de.

In the pathogenesis of autoimmune type 1 diabetes, the apoptosis receptor Fas appears de novo on the surface of insulin-producing ß-cells. Fas expression is thought to be induced by proinflammatory cytokines, such as IL-1ß, interferon- (IFN), and TNF, released by islet-infiltrating mononuclear cells. To determine whether ß-cells can modulate their sensitivity to apoptosis at the level of Fas, we investigated the effect of Fas ligand (FasL) on surface expression of Fas in NIT-1 insulinoma cells from nonobese diabetic (NOD) mice prone to autoimmune diabetes and islet cells from NOD and nonautoimmune BALB/c mice. In NIT-1 insulinoma cells, Fas expression induced by the cytokine combination IL-1ß and IFN was reduced in the presence of FasL, whereas in islet cells Fas expression was unaffected by FasL. The effect of FasL on NIT-1 cells was evident during and after the induction of Fas expression by IL-1ß and IFN. Thus, FasL down-regulates cytokine-induced Fas expression in NOD mouse-derived NIT-1 cells, but not in NOD or BALB/c mouse islets. The ability of NIT-1 cells to down-regulate Fas receptor in response to ligation is similar to that of a variety of tumor cells, which may use this mechanism to escape destruction by cytotoxic T cells. Islets apparently cannot protect themselves against FasL-induced apoptosis by down-regulating the Fas receptor. Understanding how NIT-1 insulinoma cells down-regulate Fas receptor in response to ligation by FasL has therapeutic implications for protecting normal ß-cells in autoimmune type 1 diabetes.

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