TY - JOUR
T1 - IL-12 administration accelerates autoimmune diabetes in both wild-type and IFN-γ-deficient nonobese diabetic mice, revealing pathogenic and protective effects of IL-12-induced IFN-γ
AU - Trembleau, Sylvie
AU - Penna, Giuseppe
AU - Gregori, Silvia
AU - Giarratana, Nadia
AU - Adorini, Luciano
PY - 2003/6/1
Y1 - 2003/6/1
N2 - IL-12 administration to nonobese diabetic (NOD) mice induces IFN-γ-secreting type 1 T cells and high circulating IFN-γ levels and accelerates insulin-dependent diabetes mellitus (IDDM). Here we show that IL-12-induced IFN-γ production is dispensable for diabetes acceleration, because exogenous IL-12 could enhance IDDM development in IFN-γ-deficient as well as in IFN-γsufficient NOD mice. Both in IFN-γ+/- and IFN-γ-/- 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-α. Surprisingly, IL-12-induced IFN-γ 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-γ-/- 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-γ+/- mice because IL-12 administration in the absence of IFN-γ leads to enhanced cell proliferation and reduced T cell apoptosis. NO, an effector molecule in β cell destruction, is produced ex vivo in high quantity by pancreasinfiltrating cells through a mechanism involving IL-12-induced IFN-γ. Conversely, in IL-12-treated IFN-γ-deficient mice, other pathways of β cell death appear to be increased, as indicated by the up-regulated expression of Fas ligand on Th1 cells in the absence of IFN-γ. These data demonstrate that IFN-γ has a dual role, pathogenic and protective, in IDDM development, and its deletion allows IL-12 to establish alternative pathways leading to diabetes acceleration.
AB - IL-12 administration to nonobese diabetic (NOD) mice induces IFN-γ-secreting type 1 T cells and high circulating IFN-γ levels and accelerates insulin-dependent diabetes mellitus (IDDM). Here we show that IL-12-induced IFN-γ production is dispensable for diabetes acceleration, because exogenous IL-12 could enhance IDDM development in IFN-γ-deficient as well as in IFN-γsufficient NOD mice. Both in IFN-γ+/- and IFN-γ-/- 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-α. Surprisingly, IL-12-induced IFN-γ 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-γ-/- 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-γ+/- mice because IL-12 administration in the absence of IFN-γ leads to enhanced cell proliferation and reduced T cell apoptosis. NO, an effector molecule in β cell destruction, is produced ex vivo in high quantity by pancreasinfiltrating cells through a mechanism involving IL-12-induced IFN-γ. Conversely, in IL-12-treated IFN-γ-deficient mice, other pathways of β cell death appear to be increased, as indicated by the up-regulated expression of Fas ligand on Th1 cells in the absence of IFN-γ. These data demonstrate that IFN-γ has a dual role, pathogenic and protective, in IDDM development, and its deletion allows IL-12 to establish alternative pathways leading to diabetes acceleration.
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M3 - Article
C2 - 12759426
AN - SCOPUS:0037514387
VL - 170
SP - 5491
EP - 5501
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 11
ER -