Immunoregulation during disease progression in prediabetic NOD mice: inverse expression of arginase and prostaglandin H synthase 2 vs. interleukin-15.
Non-obese diabetic (NOD) mice spontaneously develop insulin dependent diabetes due to autoimmune destruction of beta-cells. The progression of insulitis can be accelerated and synchronized in the pancreas by a single injection of 250 mg/kg cyclophosphamide. In this study, we will report on three immune mediators that were not known to be expressed during insulitis until now. Early insulitis in ten-week-old female NOD mice was associated with strong expression of prostaglandin H synthase 2 in the pancreas and of arginase, an antagonist enzyme of the inducible NO synthase. After acceleration of insulitis progression by cyclophosphamide, expression of the two enzymes was downregulated within 24 h. There was strong concomitant upregulation of IL-15 gene expression that preceded lymphocyte invasion of islets and a rise of IFN-gamma mRNA levels by several days. The comparison of individual pancreata showed that the expression of IL-12 and IL-18 mRNA closely correlated with levels of IL-15 gene expression. We conclude that arginase and prostaglandin H synthase 2 expression is associated with peri-insulitis, while IL-15 is a candidate cytokine in driving destructive insulitis, as it elicits Th1-cytotoxic responses in lymphoid as well as in non-lymphoid immune cells and is unusually resistant to downregulation by antagonistic cytokines. This is the first report on arginase, prostaglandin H synthase 2 and IL-15 expression in pancreatic lesions of prediabetic NOD mice.
Rothe
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Germany Diabetes Research Institute, Heinrich Heine University of Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany.
Hausmann
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Kolb
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D000818:Animals; D001119:Arginase / Q000096:biosynthesis* / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006651:Histocytochemistry; D019409:Interleukin-15 / Q000096:biosynthesis* / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000201:enzymology / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D015854:Up-Regulation
D019409:Interleukin-15; D007378:Interleukins; D012333:RNA, Messenger; D011451:Prostaglandin-Endoperoxide Synthases; D001119:Arginase