Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

Ymer, Susie I.; Huang, Dexing; Penna, Giuseppe; Gregori, Silvia; Branson, Kristin; Adorini, Luciano; Morahan, Grant

doi:10.1038/sj.gene.6363849

Cited by 28 publications

(23 citation statements)

References 27 publications

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“…Indeed, sequence variations in the coding region of the p40 gene between different inbred strains of mice have recently been identified. 12,21 Finally, it is unlikely that the observed differences in p70 secretion are mediated through differential p35 expression, since the IL-12 p35 gene is located on another chromosome than the p40 gene.…”

Section: Discussionmentioning

confidence: 99%

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

et al. 2002

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Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. We evaluated whether a TaqI polymorphism in the 3 0 UTR of the IL-12 p40 gene affects secretion of IL-12 in vitro, and whether this polymorphism is associated with susceptibility to Crohn's disease (CD). IL-12 p40 and p70 secretion by monocytes in relation to genotype was determined in 63 healthy donors. Genotype and allele frequencies of the TaqI polymorphism in 150 CD patients were compared with 145 ethnically matched healthy controls (HC). No significant association was found between genotype and IL-12 p40 secretion after stimulation of monocytes with SAC+IFNg. In contrast, increasing IL-12 p70 secretion was found across the categories of noncarriers, heterozygotes and homozygotes for the variant allele (median values 7 SEM: 147 7 27, 282 7 51 and 482 7 34 pg/ ml, respectively; Po0.005). The allele and genotype frequencies of this polymorphism in patients with CD did not differ statistically significantly from HC. The presence of a TaqI polymorphism in the IL12 p40 3 0 UTR correlates with increased in vitro IL-12 p70, but not p40 secretion. While this polymorphism does not appear to be correlated with susceptibility to CD in the limited population of patients tested here, it could influence the occurrence of the disease in certain subsets of patients.

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Section: Discussionmentioning

confidence: 99%

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

et al. 2002

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“…For example, Th1 cells are the main initiators of insulitis, the lymphocytic infiltrate that may be observed in pancreatic islets prior to diabetes development. 17,18 With the demonstration of IL-12 in T1D development in animal models and the identification of IL12B as a susceptibility locus in humans, 8,19 and of differential IL-12 gene expression in humans 8,19 and mice, 20 other genes in the IL-12 pathway also become candidates for involvement in T1D. We successfully applied SSCP screening to identify genetic polymorphisms within the IL12RB1 gene.…”

Section: Discussionmentioning

confidence: 99%

Definition of polymorphisms in the gene encoding the interleukin-12 receptor B1 subunit: testing linkage disequilibrium with Type I diabetes susceptibility

Tabone

Morahan

2003

Genes Immun

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The cytokine interleukin (IL)-12 is bound by a heterodimeric receptor and mediates a range of immunological activities, in particular, favouring the development of uncommitted T cells to the Th1 phenotype. Genes encoding elements of the IL-12 pathway are therefore good candidates for mediating susceptibility or resistance to a range of immune disorders, including Type I diabetes. We made a systematic search for variants in the human gene encoding the low-affinity IL-12 receptor, IL12RB1. Four single-nucleotide polymorphisms and two microsatellite polymorphisms were defined. We also tested these IL12RB1 alleles for involvement in Type I diabetes susceptibility, testing 131 families. Although suggestive evidence for linkage to a susceptibility gene was found, none of the IL12RB1 variants we defined demonstrated preferential transmission in these families.

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“…In addition, IL-12 mRNA increases in the islets in parallel to ␤ cell destruction (7). The IL-12p40 chain of NOD and other autoimmune disease-prone mice carries two amino acid substitutions compared with NOR and other mouse strains, and IL-12p40 levels, both basal and induced, are reduced in the NOD mouse (8). Reduced levels of the potentially inhibitory IL-12p40 chain coupled with enhanced production of the IL-12p75 heterodimer could explain the enhanced Th1 cell development observed in the NOD mouse (8 -10).…”

Section: Il-12 Administration Accelerates Autoimmune Diabetes In Bothmentioning

confidence: 99%

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

Trembleau

Penna

Gregori

et al. 2003

The Journal of Immunology

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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-γ-sufficient 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 pancreas-infiltrating 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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Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

Abstract: Interleukin (Il)-12 is a heterodimeric cytokine composed of 35 and 40 kD chains that plays a key role in the induction

Cited by 28 publications

References 27 publications

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

Definition of polymorphisms in the gene encoding the interleukin-12 receptor B1 subunit: testing linkage disequilibrium with Type I diabetes susceptibility

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

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