IL-12 plays a pathologic role at the inflammatory loci in the development of diabetes in NOD mice.
Accumulating evidence suggests that CD4(+)T helper type 1 (Th1) cells play a major role in the development of insulin-dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse model. Interleukin (IL)-12 is a potent immunoregulatory molecule that is a key determinant of T-cell differentiation into Th1 cells, and has been implicated in the development of IDDM. To investigate the role of IL-12 that is locally produced by islet-infiltrating cells in the development of IDDM, we generated transgenic NOD mice in which the IL-12 p40 homodimer, a natural antagonist of IL-12, was produced exclusively in islets without affecting the levels of IL-12 p40 in the systemic circulation. We found that the incidence of diabetes was significantly reduced in these transgenic mice. These results clearly demonstrate that IL-12 locally produced by islet-infiltrating cells plays a critical role in the development of IDDM.
Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Suita, Osaka 565-0871, Japan.
Y
Y
Nitta
S
S
Kawamoto
F
F
Tashiro
H
H
Aihara
T
T
Yoshimoto
H
H
Nariuchi
K
K
Tabayashi
J
J
Miyazaki
D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology*; D019281:Dimerization; D005260:Female; D015870:Gene Expression; D005934:Glucagon; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015994:Incidence; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic
D007166:Immunosuppressive Agents; D018664:Interleukin-12; D003520:Cyclophosphamide; D005934:Glucagon