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

Eur J Immunol. 2003 Aug;33(8):2278-86. doi: 10.1002/eji.200323864.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / etiology*
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / prevention & control
  • Glycoproteins / pharmacology*
  • Humans
  • Hyperglycemia / prevention & control
  • In Vitro Techniques
  • Intercellular Signaling Peptides and Proteins
  • Interferon-gamma / biosynthesis
  • Interleukin-1 / biosynthesis
  • Interleukin-18 / blood
  • Interleukin-18 / physiology*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / pathology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide / biosynthesis
  • Recombinant Fusion Proteins / pharmacology
  • Spleen / drug effects
  • Spleen / physiology
  • Streptozocin / administration & dosage
  • Streptozocin / toxicity
  • Time Factors


  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-1
  • Interleukin-18
  • Recombinant Fusion Proteins
  • interleukin-18 binding protein
  • Nitric Oxide
  • Streptozocin
  • Interferon-gamma