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• W2595309751 abstract "The ubiquitin homolog, Isg15 is up-regulated in the endometrium in response to pregnancy in humans, baboons, ruminants, pigs, and mice. Isg15 is produced in response to type I interferon (IFN), becomes covalently attached to intracellular proteins (isgylation) and regulates numerous intracellular responses. The purposes of this study were to: 1) solidify a functional role for Isg15 during pregnancy using Isg15 mutant mice; 2) identify cytokines that regulate Isg15 expression during decidualization; and 3) identify pathways negatively impacted by Isg15 deficiency in vivo. We previously reported up to 70% embryo mortality in Isg15 knockout (KO) female mice when mated to either wild type (WT) or KO males. More recently, and in response to low relative humidity (<30%), the average litter size was reduced 36 % in Isg15 KO females compared to WT. Embryo mortality was also increased 1.5 fold in KO females kept under hypoxic conditions. Our findings using two different model systems indicate that Isg15 functions to assist mothers in coping with stressors imposed on pregnancy by the environment. IL-1β initiates murine and human decidualization responses. It was next hypothesized that IL-1β induces isgylation in cultured mouse decidual explants and in human uterine fibroblast (HuF) cells. Culture of mouse decidual explants (7.5 dpc) or HuF cells with 10 ng/mL IL-1β induced an increase in Isg15 mRNA. In parallel, IL-1β up-regulated expression of enzymes (Herc5, Ubch8) that coordinate the covalent addition of Isg15 to target proteins, as well as the gene that encodes the de-isglyation enzyme UBP43 in HuF cells. In a final series of experiments qRT-PCR was used to validate expression of select genes identified in our previous microarray analysis. Here ~500 genes were differentially expressed in Isg15 KO versus WT deciduas on 7.5 dpc. We confirmed that Ifi202b, an anti-apoptotic and cell-survival gene is up-regulated and that Adam8 and Adam12 are down-regulated in decidual tissue isolated from Isg15 KO. Adam12 is a disintegrin that functions primarily in adhesion. However, Adam12 also releases IGF1 from IGFBP3 and is inversely correlated with pre-eclampsia and intra-uterine growth restriction in humans. In summary, Isg15 KO mothers are less able to cope with environmental stressors such as low humidity and hypoxia. Mutant Isg15 mice have been invaluable to our search for factors that regulate Isg15 expression during pregnancy, and in identifying pathways that are targets of Isg15 function. The authors thank Dr. A.T. Fazleabas for providing the HuF cells." @default.
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• W2595309751 date "2008-05-01" @default.
• W2595309751 modified "2023-09-26" @default.
• W2595309751 title "Isg15 Is a Molecular Sentinel That Functions to Assist Mothers in Coping with Environmental Stressors Imposed on Pregnancy." @default.
• W2595309751 doi "https://doi.org/10.1093/biolreprod/78.s1.172a" @default.
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