IL-18 Inhibits Diabetes Development in Nonobese Diabetic Mice by Counterregulation of Th1-Dependent Destructive Insulitis

The development of type 1 diabetes in animal models is T cell and macrophage dependent. Islet inflammation begins as peripheral benign Th2 type insulitis and progresses to destructive Th1 type insulitis, which is driven by the innate immune system via secretion of IL-12 and IL-18. We now report that...

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Bibliographic Details
Published in:The Journal of immunology (1950) 1999-08, Vol.163 (3), p.1230-1236
Main Authors: Rothe, Helga, Hausmann, Andreas, Casteels, Kristina, Okamura, Hakuri, Kurimoto, Masashi, Burkart, Volker, Mathieu, Chantal, Kolb, Hubert
Format: Article
Language:English
Subjects:
Animals
Cytokines - biosynthesis
Cytokines - genetics
Diabetes Mellitus, Type 1 - enzymology
Diabetes Mellitus, Type 1 - immunology
Diabetes Mellitus, Type 1 - pathology
Diabetes Mellitus, Type 1 - prevention & control
Female
Hypoglycemic Agents - administration & dosage
Hypoglycemic Agents - immunology
Injections
Interleukin-18 - administration & dosage
Interleukin-18 - biosynthesis
Interleukin-18 - genetics
Interleukin-18 - physiology
Islets of Langerhans - immunology
Islets of Langerhans - pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred NOD
Nitric Oxide Synthase - biosynthesis
Nitric Oxide Synthase - genetics
Nitric Oxide Synthase Type II
Prediabetic State - immunology
Prediabetic State - pathology
RNA, Messenger - biosynthesis
Th1 Cells - enzymology
Th1 Cells - immunology
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Summary:The development of type 1 diabetes in animal models is T cell and macrophage dependent. Islet inflammation begins as peripheral benign Th2 type insulitis and progresses to destructive Th1 type insulitis, which is driven by the innate immune system via secretion of IL-12 and IL-18. We now report that daily application of IL-18 to diabetes-prone female nonobese diabetic mice, starting at 10 wk of age, suppresses diabetes development (p < 0.001, 65% in sham-treated animals vs 33% in IL-18-treated animals by 140 days of age). In IL-18-treated animals, we detected significantly lower intraislet infiltration (p < 0.05) and concomitantly an impaired progression from Th2 insulitis to Th1-dependent insulitis, as evidenced from IFN-gamma and IL-10 mRNA levels in tissue. The deficient progression was probably due to lesser mRNA expression of the Th1 driving cytokines IL-12 and IL-18 by the innate immune system (p < 0.05). Furthermore, the mRNA expression of inducible NO synthase, a marker of destructive insulitis, was also not up-regulated in the IL-18-treated group. IL-18 did not exert its effect at the levels of islet cells. Cultivation of islets with IL-18 affected NO production or mitochondrial activity and did not protect from the toxicity mediated by IL-1beta, TNF-alpha, and IFN-gamma. In conclusion, we show for the first time that administration of IL-18, a mediator of the innate immune system, suppresses autoimmune diabetes in nonobese diabetic mice by targeting the Th1/Th2 balance of inflammatory immune reactivity in the pancreas.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.163.3.1230