Transgenic expression of IL-10 in pancreatic islet A cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice.
To study the paracrine effect of IL-10 on autoimmune insulitis and diabetes, we produced IL-10 transgenic non-obese diabetic (NOD) mice (NOD-IL-10) in which murine IL-10 was expressed in pancreatic islet A cells under the control of a rat glucagon promoter without directly manipulating pancreatic islet B cells. Among 11 founder mice, four of four males and three of seven females developed diabetes by 10 weeks of age. Histological analysis of six NOD-IL-10 revealed severe insulitis and prominent ductal proliferation. NOD-IL-10 also showed spotty lymphocytic infiltration in the lung and liver in four of six founder mice. The onset of diabetes in NOD-IL-10 was remarkably earlier than that of 14 weeks of age at the earliest in female non-transgenic NOD mice. When the NOD-IL-10 mouse was backcrossed to C57BL/6 mice, none of the resulting F1, B-N2 or B-N3 generation toward C57BL/6 mice showed diabetes even at 39 weeks of age, in spite of the presence of peri-insulitis and prominent ductal proliferation, while two of four mice of the N-N2 generation toward NOD mice showed early-onset diabetes. Thus, transgenic paracrine expression of IL-10 in situ in the NOD genetic background enhances autoimmune insulitis and diabetes in their onset and severity, ignoring gender difference. Because expression of IL-10 was detected by polymerase chain reaction in pancreatic islets of non-transgenic NOD mice after 5 weeks of age, IL-10 secreted in situ is regarded to enhance cell-mediated autoimmune diabetes, in spite of established in vitro anti-Th1 activity of IL-10.
Moritani
M
M
Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, University of Tokushima, Japan.
Yoshimoto
K
K
Tashiro
F
F
Hashimoto
C
C
Miyazaki
J
J
Ii
S
S
Kudo
E
E
Iwahana
H
H
Hayashi
Y
Y
Sano
T
T
D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D007249:Inflammation / Q000276:immunology; D007328:Insulin; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis
D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D016753:Interleukin-10