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Earlier studies have shown direct effects of interleukin-1 (IL-1) on isolated pancreatic islets. Coculture of isolated rat pancreatic islets with human rIL-1β for 6 days resulted in dose-dependent cytotoxicity (up to 100%) and suppression of insulin secretion (up to 88.5%). The cytotoxic effects of rIL-1β were blocked by the simultaneous presence of a naturally occurring 6- 9-kilodalton (kDa) inhibitor of IL-1-induced T-cell proliferation. However, the ability of rIL-1β to suppress insulin secretion was not blocked by the 6-9-kDa inhibitor of IL-1 activity. This IL-1 inhibitor is produced by mononuclear cells and is resistant to pH 2, sensitive to heating at 56°C for 30 min, has a pi of 4.5-5.6, and appears to be different from other recognized IL-1 inhibitors in both composition and mechanism of action. Unlike this IL-1 inhibitor, a monoclonal antibody specific for rIL-1β was able to neutralize both the islet cytotoxic and insulin modulatory effects of rIL-1β. These results demonstrate the use of an IL-1 inhibitor to prevent at least one mechanism of islet destruction, and suggest separate pathways for IL-1-mediated islet cytotoxicity and suppression of insulin secretion.