Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models
| العنوان: | Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models |
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| المؤلفون: | Stefan Siwko, Xinyan Zhang, Mingyao Liu, Xia Li, Shijie Liu, Dali Li, Na Gao, Liang Li, Gaigai Wei, Ganglong Gao, Zhaohua Chen, Xueyun Ma, Yuting Guan, Yansen Zheng, Long Zhang, Jinlian Chen |
| المصدر: | The Journal of Immunology. 195:339-346 |
| بيانات النشر: | The American Association of Immunologists, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | STAT3 Transcription Factor, Immunology, Mice, Transgenic, Haploinsufficiency, mTORC1, Mechanistic Target of Rapamycin Complex 1, Biology, Inflammatory bowel disease, Mice, medicine, Animals, Humans, Immunology and Allergy, Colitis, PI3K/AKT/mTOR pathway, Bone Marrow Transplantation, Cell Proliferation, Monomeric GTP-Binding Proteins, Sirolimus, Interleukin-6, Cell growth, TOR Serine-Threonine Kinases, Regeneration (biology), Neuropeptides, Sodium Dodecyl Sulfate, medicine.disease, Survival Analysis, Mice, Inbred C57BL, Gene Expression Regulation, Trinitrobenzenesulfonic Acid, Multiprotein Complexes, Cancer research, biology.protein, Ras Homolog Enriched in Brain Protein, Caco-2 Cells, biological phenomena, cell phenomena, and immunity, Signal transduction, Signal Transduction, RHEB |
| الوصف: | The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues to regulate cell growth and survival through various mechanisms. However, how mTORC1 responds to acute inflammatory signals to regulate bowel regeneration is still obscure. In this study, we investigated the role of mTORC1 in acute inflammatory bowel disease. Inhibition of mTORC1 activity by rapamycin treatment or haploinsufficiency of Rheb through genetic modification in mice impaired intestinal cell proliferation and induced cell apoptosis, leading to high mortality in dextran sodium sulfate– and 2,4,6-trinitrobenzene sulfonic acid–induced colitis models. Through bone marrow transplantation, we found that mTORC1 in nonhematopoietic cells played a major role in protecting mice from colitis. Reactivation of mTORC1 activity by amino acids had a positive therapeutic effect in mTORC1-deficient Rheb+/− mice. Mechanistically, mTORC1 mediated IL-6–induced Stat3 activation in intestinal epithelial cells to stimulate the expression of downstream targets essential for cell proliferation and tissue regeneration. Therefore, mTORC1 signaling critically protects against inflammatory bowel disease through modulation of inflammation-induced Stat3 activity. As mTORC1 is an important therapeutic target for multiple diseases, our findings will have important implications for the clinical usage of mTORC1 inhibitors in patients with acute inflammatory bowel disease. |
| تدمد: | 1550-6606 0022-1767 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0febdc3aed14f371ffa036eeddcad73f https://doi.org/10.4049/jimmunol.1303356 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0febdc3aed14f371ffa036eeddcad73f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
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