| First Author | Trembleau S | Year | 2003 |
| Journal | J Immunol | Volume | 170 |
| Issue | 11 | Pages | 5491-501 |
| PubMed ID | 12759426 | Mgi Jnum | J:83456 |
| Mgi Id | MGI:2662049 | Doi | 10.4049/jimmunol.170.11.5491 |
| Citation | Trembleau S, et al. (2003) IL-12 Administration Accelerates Autoimmune Diabetes in Both Wild-Type and IFN-gamma-Deficient Nonobese Diabetic Mice, Revealing Pathogenic and Protective Effects of IL-12-Induced IFN-gamma. J Immunol 170(11):5491-501 |
| abstractText | IL-12 administration to nonobese diabetic (NOD) mice induces IFN-gamma-secreting type 1 T cells and high circulating IFN-gamma levels and accelerates insulin-dependent diabetes mellitus (IDDM). Here we show that IL-12-induced IFN-gamma production is dispensable for diabetes acceleration, because exogenous IL-12 could enhance IDDM development in IFN-gamma-deficient as well as in IFN-gamma-sufficient NOD mice. Both in IFN-gamma(+/-) and IFN-gamma(-/-) NOD mice, IL-12 administration generates a massive and destructive insulitis characterized by T cells, macrophages, and CD11c(+) dendritic cells, and increases the number of pancreatic CD4(+) cells secreting IL-2 and TNF-alpha. Surprisingly, IL-12-induced IFN-gamma hinders pancreatic B cell infiltration and inhibits the capacity of APCs to activate T cells. Although pancreatic CD4(+) T cells from IL-12-treated IFN-gamma(-/-) mice fail to up-regulate the P-selectin ligand, suggesting that their entry into the pancreas may be impaired, T cell expansion is favored in these mice compared with IL-12-treated IFN-gamma(+/-) mice because IL-12 administration in the absence of IFN-gamma leads to enhanced cell proliferation and reduced T cell apoptosis. NO, an effector molecule in beta cell destruction, is produced ex vivo in high quantity by pancreas-infiltrating cells through a mechanism involving IL-12-induced IFN-gamma. Conversely, in IL-12-treated IFN-gamma-deficient mice, other pathways of beta cell death appear to be increased, as indicated by the up-regulated expression of Fas ligand on Th1 cells in the absence of IFN-gamma. These data demonstrate that IFN-gamma has a dual role, pathogenic and protective, in IDDM development, and its deletion allows IL-12 to establish alternative pathways leading to diabetes acceleration. |
