Destruction of Rat Islet Cell Monolayers by Cytokines. Synergistic Interactions of Interferon-gamma, Tumor Necrosis Factor, Lymphotoxin, and Interleukin 1

An assay was developed to detect the cytotoxic effects of cytokines on rat pancreatic islet cells in monolayer culture. Cell lysis was detected by a 51Cr-release assay after 4 days of incubation with various cytokines. When tested alone, murine (rat and mouse) interferon-gamma (mIFN-gamma) produced a small dose-dependent lysis of islet cells; human IFN-gamma, mouse IFN-alpha/beta, interleukins 1 and 2 (IL-1 and IL-2), tumor necrosis factor (TNF), and lymphotoxin (LT) were inactive. When added together, the following combinations of cytokines showed synergistic cytotoxic effects: TNF (or LT) plus IL-1, TNF (or LT) plus mIFN-gamma, and IL-1 plus mIFN-gamma. These results indicate that the cytokine products of mononuclear cells of the immune system, IFN-gamma, TNF, LT, and IL-1 have strong synergistic cytotoxic effects on islet cells and therefore may act as direct chemical mediators of islet beta-cell destruction in type I (insulin-dependent) diabetes.