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.
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.
Nicoletti
Ferdinando
F
Department of Biomedical Sciences, University of Catania, Catania, Italy. ferdinic@unict.it
Di Marco
Roberto
R
Papaccio
Gianpaolo
G
Conget
Ignacio
I
Gomis
Ramon
R
Bernardini
Renato
R
Sims
John E
JE
Shoenfeld
Yehuda
Y
Bendtzen
Klaus
K
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000097:blood / Q000502:physiology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013311:Streptozocin / Q000008:administration & dosage / Q000633:toxicity; D013997:Time Factors
D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D020382:Interleukin-18; D011993:Recombinant Fusion Proteins; C118370:interleukin-18 binding protein; D009569:Nitric Oxide; D013311:Streptozocin; D007371:Interferon-gamma