title: Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models.
abstract: 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.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Yuting
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Xinyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Shijie
authors.initials: S
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Na
authors.initials: N
authors.lastname: Gao
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Fengxian Hospital, Southern Medical University, Shanghai 201499, China; and.
authors.forename: Ganglong
authors.initials: G
authors.lastname: Gao
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Gaigai
authors.initials: G
authors.lastname: Wei
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Yansen
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China;
authors.forename: Xueyun
authors.initials: X
authors.lastname: Ma
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030.
authors.forename: Stefan
authors.initials: S
authors.lastname: Siwko
authors.affiliation: Fengxian Hospital, Southern Medical University, Shanghai 201499, China; and dlli@bio.ecnu.edu.cn wqq_021002@163.com.
authors.forename: Jin-Lian
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China; Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China; dlli@bio.ecnu.edu.cn wqq_021002@163.com.
authors.forename: Dali
authors.initials: D
authors.lastname: Li
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D005786:Gene Expression Regulation; D057895:Haploinsufficiency; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020559:Monomeric GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000076205:Ras Homolog Enriched in Brain Protein; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D012967:Sodium Dodecyl Sulfate; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D015850:Interleukin-6; D046912:Multiprotein Complexes; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D012967:Sodium Dodecyl Sulfate; D014302:Trinitrobenzenesulfonic Acid; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D020123:Sirolimus