In the pathogenesis of autoimmune type 1 diabetes, the apoptosis receptor Fas appears de novo on the surface of insulin-producing cells. Fas expression is thought to be induced by pro-inflammatory cytokines such as IL-1, IFN- and TNF- released by islet-infiltrating mononuclear cells. To determine whether cells can modulate their sensitivity to apoptosis at the level of Fas, we investigated the effect of FasL on surface expression of Fas in NIT-1 insulinoma cells from NOD mice prone to autoimmune diabetes and islet cells from NOD and non-autoimmune BALB/c mice. In NIT-1 insulinoma cells, Fas expression induced by the cytokine combination IL-1 and IFN- was reduced in the presence of FasL, whereas in islet cells Fas expression was unaffected by FasL. The effect of FasL in NIT-1 cells was evident during and after the induction of Fas expression by IL-1 and IFN-. Thus, FasL downregulates 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 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 downregulating 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 cells in autoimmune type 1 diabetes.