Complete suppression of insulitis and diabetes in NOD mice lacking interferon regulatory factor-1.
Interferon regulatory factor-1 (IRF-1), a transcriptional factor, regulates type I interferon and interferon-induced genes. It was reported that IRF-1 regulates important molecules required for inflammation and immune reactions. To investigate the role of IRF-1 in the development of autoimmune diabetes, we established IRF-1 deficient (IRF-1(-/-)) non-obese diabetic (NOD) mice. IRF-1-deficient C57BL/6J mice were out-crossed to NOD mice, and F1 were backcrossed to NOD mice. At the N8 generation, the heterozygote for IRF-1 mutation was intercrossed and N8F1 was obtained. Out of three NOD genotypes, IRF-1(+/+) and IRF-1(+/-) developed spontaneous diabetes with an incidence of 47% (9/19) and 50% (10/20) by 30 weeks of age, respectively; whereas IRF-1(-/-) did not develop diabetes (0/18, P< 0.01 vs. (+/+) and (+/-)). Histologically, IRF-1(+/+) and IRF-1(+/-) had various degrees of insulitis, but IRF-1(-/-) had no insulitis. In comparison with IRF-1(+/+), the percentage of CD4(+) and Mac-1(+) splenic cells significantly increased, whereas CD3(+), CD8(+) and B220(+) cells decreased in IRF-1(-/-). Furthermore, spleen cell proliferation in response to Con A or murine GAD65 peptide, a major autoantigen of the pancreatic beta-cell, significantly increased, and the IFN-gamma/IL-10 ratio in the culture supernatant significantly decreased in IRF-1(-/-), suggesting Th2 deviation in cytokine balance. These results indicate that IRF-1 plays a key role in developing insulitis and diabetes in NOD mice.
Nakazawa
T
T
Division of Molecular Metabolism and Diabetes, Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Satoh
J
J
Takahashi
K
K
Sakata
Y
Y
Ikehata
F
F
Takizawa
Y
Y
Bando
S I
SI
Housai
T
T
Li
Y
Y
Chen
C
C
Masuda
T
T
Kure
S
S
Kato
I
I
Takasawa
S
S
Taniguchi
T
T
Okamoto
H
H
Toyota
T
T
D000818:Animals; D002455:Cell Division / Q000276:immunology; D003208:Concanavalin A / Q000276:immunology; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics*; D050856:Interferon Regulatory Factor-1; D007515:Islets of Langerhans / Q000473:pathology*; D007527:Isoenzymes / Q000737:chemistry / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D018895:Microsatellite Repeats / Q000235:genetics; D010455:Peptides / Q000276:immunology; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics*; D013154:Spleen / Q000737:chemistry / Q000166:cytology / Q000276:immunology
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D007527:Isoenzymes; D010455:Peptides; D010750:Phosphoproteins; D003208:Concanavalin A; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2