Bacteria‐ and host‐derived signals converge at the epithelial cell level and play a critical role in the initiation and regulation of chronic intestinal inflammation. We used epithelial cell proteomics in Enterococcus faecalis‐monoassociated IL‐10−/− and wild type mice to identify novel targets of the disease pathology. Interestingly, primary IEC from IL‐10−/− mice as well as IBD patients revealed increased expression levels of the glucose‐regulated ER stress protein (grp)‐78 under conditions of chronic inflammation. Consistent with the observation that TNF induced ER stress responses through grp‐78 redistribution from the ER lumen to the cytoplasmic IkappaB kinase complex, grp‐78 knock‐down completely abolished TNF‐induced NF‐kappaB RelA phosphorylation. Interestingly, IL‐10 inhibited grp‐78 expression in IL‐10 receptor reconstituted IEC. Chromatin immunoprecipitation analysis and immunofluorescence microscopy revealed that IL‐10‐mediated p38 signaling inhibited TNF‐induced recruitment of the ER‐derived activating transcription factor (ATF)‐6 to the grp‐78 promoter likely through the blockade of ATF‐6 nuclear translocation. In conclusion, the initiation of ER‐mediated stress responses in the intestinal epithelium may contribute to the pathogenesis of chronic intestinal inflammation.
DM prognostication, and remained statistically significant after multivariable adjustment. RS had improved predictive value for DMFS in the HPV-negative subgroup (HR 20.8; 95% CI, 2.6-166, P Z 0.004). Conclusion: We have identified and validated a group of genes that predict distant metastasis among loco-regionally advanced HNSCC tumors. This score offers a prognostic tool for detecting a group of HNSCC patients at high risk for DM who may benefit from intensified monitoring and/or treatment.
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