Protective Role of p70S6K in Intestinal Ischemia/Reperfusion Injury in Mice

Ban, Kechen; Kozar, Rosemary A.

doi:10.1371/journal.pone.0041584

Cited by 24 publications

(33 citation statements)

References 60 publications

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“…1A). This is consistent with the report that mTOR is activated in intestinal ischemia-and irradiation-induced intestinal regeneration (37,38). Inhibition of mTORC1 activity by either rapamycin treatment or haploinsufficiency of Rheb in mice resulted in increased apoptosis and decreased cell proliferation, leading to more severe tissue damage in our DSS-or TBNS-induced colitis models.…”

Section: Discussionsupporting

confidence: 92%

“…1B), suggesting that S6K1 is probably the key player downstream of mTORC1. Similar results have been reported in intestinal ischemia/ reperfusion injury and LPS-induced lung injury, further supporting our speculation (38,39). Recently, Faller et al (40), using multiple genetically engineered mouse alleles, found that S6K1/2, but not 4EBP1/2, was involved in intestinal regeneration and demonstrated that rapamycin functioned mainly through the mTORC1-S6K pathway rather than through the 4EBP1-eIF4E branch.…”

Section: Discussionsupporting

confidence: 90%

See 1 more Smart Citation

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

Guan

Zhang

et al. 2015

The Journal of Immunology

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

Guan

Zhang

et al. 2015

The Journal of Immunology

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“…Among them, IL-6 locally produced in the intestine has been identified as a key inflammatory cytokine that plays an essential role in damaging the tissue during intestinal I/R. In support of this, it has been demonstrated that 1) both in humans (4) and in mice (5,6), local levels of IL-6 in the intestine are markedly elevated in association with severe tissue damage after intestinal I/R; 2) IL-6 Ϫ/Ϫ mice developed significantly attenuated intestinal damage after I/R; and 3) blocking IL-6 activity in WT mice using anti-IL-6 mAbs greatly retained intestinal tract integrity after I/R (7). Natural IgM has been found to be critical in the pathogenesis of intestinal I/R.…”

mentioning

confidence: 90%

CD6 Receptor Regulates Intestinal Ischemia/Reperfusion-induced Injury by Modulating Natural IgM-producing B1a Cell Self-renewal

Enyindah-Asonye

Wei

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillIntestinal ischemia/reperfusion (I/R) injury is a relatively common pathological condition that can lead to multi-organ failure and mortality. Regulatory mechanism for this disease is poorly understood, although it is established that circulating pathogenic natural IgM, which is primarily produced by B1a cells outside of the peritoneal cavity, are integrally involved. CD6 was originally identified as a marker for T cells and was later found to be present on some subsets of B cells in humans; however, whether CD6 plays any role in intestinal I/R-induced injury and, if so, the underlying mechanisms, remain unknown. Here we report that CD6؊/؊ mice were significantly protected from intestinal inflammation and mucosal damage compared with WT mice in a model of intestinal I/R-induced injury. Mechanistically, we found that CD6 was selectively expressed on B1 cells outside of the bone marrow and peritoneal cavity and that pathogenic natural IgM titers were reduced in the CD6 ؊/؊ mice in association with significantly decreased B1a cell population. Our results reveal an unexpected role of CD6 in the pathogenesis of intestinal IR-induced injury by regulating the self-renewal of B1a cells.

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“…The number of positively stained cells in the intestinal mucosa was counted in 50 high-power fields per section under a microscope, as described previously (33).…”

Section: F4/80-positive Cells In Colonic Mucosamentioning

confidence: 99%

Role of metallothionein in murine experimental colitis

Tsuji

Naito

Takagi

et al. 2013

International Journal of Molecular Medicine

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Abstract. Metallothioneins (MTs) are a family of cysteine-rich low molecular-weight proteins that can act as reactive oxygen species scavengers. Although it is known that the induction of MT expression suppresses various inflammatory disorders, the role of MTs in intestinal inflammation remains unclear. In this study, we investigated the effects of dextran sulfate sodium (DSS) administration in mice with targeted deletions of the MT-I/II genes. Acute colitis was induced by 2% DSS in male MT-I/II double knockout (MT-null) and C57BL/6 (wild-type) mice. The disease activity index (DAI) was determined on a daily basis for each animal, and consisted of a calculated score based on changes in body weight, stool consistency and intestinal bleeding. Histology, colon length, myeloperoxidase (MPO) activity and colonic mRNA expression and the concentration of inflammatory cytokines were evaluated by real-time-PCR and enzyme-linked immunosorbent assay (ELISA). The localization of MTs and macrophages was determined by immunohistological and immunofluorescence staining. To investigate the role of MTs in macrophages, peritoneal macrophages were isolated and their responses to lipopolysaccharide were measured. Following DSS administration, the DAI score increased in a time-dependent manner and was significantly enhanced in the MT-I/II knockout mice. Colonic MPO activity levels and inflammatory cytokines [tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-17] production increased following DSS administration, and these increases were significantly enhanced in the MT-I/II knockout mice compared with the wild-type mice. MT-positive cells were detected in the lamina propria and submucosal layer by immunohistochemical and immunofluorescence staining, and were mainly co-localized in F4/80-positive macrophages. The production of inflammatory cytokines (TNF-α, IFN-γ and IL-17) from isolated peritoneal macrophages increased following lipopolysaccharide stimulation, and these increases were significantly enhanced in the macrophages obtained from the MT-I/II knockout mice. These data indicate that MTs play an important role in the prevention of colonic mucosal inflammation in a mouse model of DSS-induced colitis, thus suggesting that endogenous MTs play a protective role against intestinal inflammation. IntroductionInflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease are known as refractory and recurrent diseases of the gastrointestinal tract. Although the features of IBDs suggest a number of possible causes, including genetic, infectious and immunological factors, the precise pathogenesis of IBDs remains unknown (1-3). Recent evidence suggests that oxidative stress caused by reactive oxygen species (ROS) is an important factor involved in the onset and development of intestinal inflammation. Furthermore, it has also been demonstrated that disruptions in the antioxidant defense system are involved in the pathophysiology of IBDs (4,5). Therefore, it is important to investigate the oxidative s...

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Protective Role of p70S6K in Intestinal Ischemia/Reperfusion Injury in Mice

Cited by 24 publications

References 60 publications

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

CD6 Receptor Regulates Intestinal Ischemia/Reperfusion-induced Injury by Modulating Natural IgM-producing B1a Cell Self-renewal

Role of metallothionein in murine experimental colitis

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