Essential pathogenic role of endogenous IL‐18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL‐18‐binding protein: Fc construct

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Abstract
IL-18 is a cytokine structurally and functionally related to IL-1 that, in synergy with IL-12, stimulates the synthesis of IFN-γ from T lymphocytes and natural killer cells. Because IFN-γ plays a key pathogenic role in the development of murine immunoinflammatory diabetes induced by multiple low doses of streptozotocin (STZ) we investigated the effect of negating the actions of endogenous IL-18 in this model by administering recombinant IL-18-binding protein:Fc (IL-18 bp:Fc). C57BL/6 mice were injected once daily with 40 mg/kg STZ for 5 consecutive days, day 0 being the first day of STZ challenge. Relative to control animals treated in parallel with either PBS or human IgG, mice treated from day –3 to day 7 with daily doses of 150 μg of IL-18 bp:Fc exhibited lowerincidence of diabetes and milder insulitis. In contrast, mice that were treated with IL-18 bp:Fc from day 7 to day 14 exhibited clinical and histological signs of STZ-induced diabetes similar to those of control mice treated with IgG. The protective effect of IL-18 bp:Fc was accompanied by modified ex vivo immune responses, in that spleen cells and peritoneal macrophages contained fewer IFN-γ secreting cells and released lower amounts of nitrite (an index of nitric oxide production) and IL-1β. We conclude that intact IL-18 function is essential for the full diabetogenic effectof low dose STZ in C57BL/6 mice.

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