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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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Ferdinando Nicoletti
  • Roberto Di Marco
  • Gianpaolo Papaccio
  • Ignacio Conget
  • Ramon Gomis
  • Renato Bernardini
  • John E Sims
  • Yehuda Shoenfeld
  • Klaus Bendtzen
IL-18 is a cytokine structurally and functionally related to IL-1 that, in synergy with IL-12, stimulates the synthesis of IFN-gamma from T lymphocytes and natural killer cells. Because IFN-gamma 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 microg of IL-18 bp:Fc exhibited lower incidence 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-gamma secreting cells and released lower amounts of nitrite (an index of nitric oxide production) and IL-1beta. We conclude that intact IL-18 function is essential for the full diabetogenic effect of low dose STZ in C57BL/6 mice.
OriginalsprogEngelsk
TidsskriftEuropean Journal of Immunology
Vol/bind33
Udgave nummer8
Sider (fra-til)2278-86
Antal sider9
ISSN0014-2980
DOI
StatusUdgivet - 1 aug. 2003

ID: 34101993