THE FUNCTIONAL-STATE OF THE BETA-CELL MODULATES IL-1 AND TNF-INDUCED CYTOTOXICITY

Insulin-dependent diabetes is an autoimmune disease specifically targe ting the pancreatic beta cells and several observations, both experime ntal and clinical, suggest that the interaction of the immune system w ith the beta cells is in part determined by the functional state of th e target cells, increased beta cell activity resulting in augmented im munologic mechanisms and vice versa for suppressed beta cell activity and decreased immune attack. In this study we investigated whether cyt okine induced islet cell cytotoxicity in vitro was in part dependent o n the functional state of the beta cells. Cytotoxicity of cultured rat islets was induced by IL-1 (100 pg/ml) and TNF(62.5 ng/ml) individual ly and in combination and beta cell activity was modulated by culturin g the islets in. media containing 3.3, 5.5, 11, and 20 mmol/liter gluc ose. Both IL-1 and TNF were cytotoxic when administered individually a nd the combination of IL-1 and TNF was more cytotoxic than either cyto kine alone. Maximum cytotoxicity was observed at 11 mmol/liter glucose with cytotoxicity being reduced at 5.5 mmol/liter glucose and further reduced at 3.3 mmol/liter glucose. Interestingly, the degree of cytot oxicity was lower in 20 mmol/liter glucose compared to 11 mmol/liter. These results firmly establish that islet cytotoxicity of IL-1 and TNF is highly dependent on the functional state of the beta cells. This s uggests that during the IDDM disease process as some beta cells are de stroyed, the compensatory increased activity of the remaining beta cel ls may increase their susceptibility to cytokine attack. Furthermore, our observations provide rational support for the use of beta cell res t as intervention therapy for IDDM.