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Aditya Garg, Angela Zhao, Sarah L Erickson, Subhajit Mukherjee, Aik Jiang Lau, Laurie Alston, Thomas K H Chang, Sridhar Mani, Simon A Hirota
The inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex etiology. IBD is thought to arise in genetically susceptible individuals in the context of aberrant interactions with the intestinal microbiota and other environmental risk factors. Recently, the pregnane X receptor (PXR) was identified as a sensor for microbial metabolites, whose activation can regulate the intestinal epithelial barrier. Mutations in NR1I2, the gene that encodes the PXR, have been linked to IBD, and in animal models, PXR deletion leads to barrier dysfunction...
October 2016: Journal of Pharmacology and Experimental Therapeutics
Bin Han, Baifa Sheng, Zhicao Zhang, Aimin Pu, Jiuheng Yin, Qimeng Wang, Kunqiu Yang, Lihua Sun, Min Yu, Yuan Qiu, Weidong Xiao, Hua Yang
BACKGROUND: Accumulating evidence suggests that the aryl hydrocarbon receptor (AhR) plays an important role in the maintenance of the function of the intestinal barrier in patients with inflammatory bowel disease and in mouse models. Intestinal obstruction (IO) is a clinical emergency consisting of severe dysfunction of intestinal barrier function, and whether AhR plays a role in the pathogenesis of IO remains unknown but would be highly significant. METHODS: Male C57BL/6 mice were subjected to IO and either treated with AhR endogenous agonist 6-formylindolo [3, 2-b] carbazole (FICZ) or left untreated...
September 2016: Shock
Takashi Nagaishi, Taro Watabe, Nisha Jose, Arisa Tokai, Toshimitsu Fujii, Katsuyoshi Matsuoka, Masakazu Nagahori, Kazuo Ohtsuka, Mamoru Watanabe
Prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). Previous studies had shown that nuclear factor-x03BA;B (NF-x03BA;B) activation in both macrophages and epithelia in inflamed colonic tissue is associated with CAC development. However, the mechanism by which epithelial NF-x03BA;B activation leading to CAC development had not previously been rigorously studied. We and others had observed the increased expression of the type 2 receptor for tumor necrosis factor (TNFR2/TNFRSF1b/p75) in IBD models...
2016: Digestion
Zaifeng Yi, Heng Fan, Xingxing Liu, Qing Tang, Dongmei Zuo, Jia Yang
Adrenomedullin (AM) is a pivotal endogenous vasoactive peptide, which can maintain epithelial barrier function in inflammatory bowel disease. Myosin light chain kinase (MLCK)‑dependent phosphorylated myosin light chain kinase (p‑MLC) is a key regulator of intestinal barrier function. The aim of the present study was to investigate the effect and mechanism of AM on the intestinal epithelial barrier in a rat model of ulcerative colitis (UC) induced by 2,4,6‑trinitro‑benzene‑sulfonic acid (TNBS). A total of 21 male Sprague‑Dawley rats were randomly divided into the following three groups and administered different agents for 7 days: The normal group (water and saline), model group (TNBS and saline) and the AM group (TNBS and AM; 1...
September 2015: Molecular Medicine Reports
Yongjian Xiong, Dapeng Chen, Changchun Yu, Bochao Lv, Jinyong Peng, Jingyu Wang, Yuan Lin
SCOPE: Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract. Citrus nobiletin can exert robust anti-inflammatory effects in vivo and in vitro. We evaluated the impact of nobiletin on the excessive inflammatory response and impaired barrier function in a rodent colitis model. METHODS AND RESULTS: Colitis was established by infusion with 1 mL 2,4,6-trinitrobenzene sulfonic acid (TNBS) dissolved in ethanol (40% v/v) in rats at a 125 mg/kg dose...
May 2015: Molecular Nutrition & Food Research
Honggang Wang, Jianning Dong, Peiliang Shi, Jianhui Liu, Lugen Zuo, Yi Li, Jianfeng Gong, Lili Gu, Jie Zhao, Liang Zhang, Wei Zhang, Weiming Zhu, Ning Li, Jieshou Li
Intestinal inflammation causes tight junction changes and death of epithelial cells, and plays an important role in the development of Crohn's disease (CD). CD52 monoclonal antibody (CD52 mAb) directly targets the cell surface CD52 and is effective in depleting mature lymphocytes by cytolytic effects in vivo, leading to long-lasting changes in adaptive immunity. The aim of this study was to investigate the therapeutic effect of CD52 mAb on epithelial barrier function in animal models of IBD. Interleukin-10 knockout mice (IL-10(-/-) ) of 16 weeks with established colitis were treated with CD52 mAb once a week for 2 weeks...
February 2015: Immunology
Masahiro Suzuki, Takashi Nagaishi, Motomi Yamazaki, Michio Onizawa, Taro Watabe, Yuriko Sakamaki, Shizuko Ichinose, Mamoru Totsuka, Shigeru Oshima, Ryuichi Okamoto, Motoyuki Shimonaka, Hideo Yagita, Tetsuya Nakamura, Mamoru Watanabe
It has been suggested that prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). We previously observed that the NF-κB activation in colonic epithelial cells is associated with increased tumor necrosis factor receptor 2 (TNFR2) expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear. Myosin light chain kinase (MLCK) has been reported to be responsible for the epithelial permeability associated with TNF signaling...
2014: PloS One
Rana Al-Sadi, Shuhong Guo, Dongmei Ye, Thomas Y Ma
Tumor necrosis factor (TNF-α) is a proinflammatory cytokine that plays a critical role in the pathogenesis of inflammatory bowel disease. TNF-α causes an increase in intestinal permeability; however, the signaling pathways and the molecular mechanisms involved remain unclear. The major purpose of this study was to investigate the role of MAP kinase pathways (ERK1/2 and p38 kinase) and the molecular processes involved. An in vitro intestinal epithelial model system consisting of Caco-2 monolayers and an in vivo mouse model system were used to delineate the cellular and molecular mechanisms involved in TNF-α effects on tight junction barrier...
December 2013: American Journal of Pathology
Liping Su, Sam C Nalle, Le Shen, Emily S Turner, Gurminder Singh, Lydia A Breskin, Ekaterina A Khramtsova, Galina Khramtsova, Pei-Yun Tsai, Yang-Xin Fu, Clara Abraham, Jerrold R Turner
BACKGROUND & AIMS: Tight junction dysregulation and epithelial damage contribute to barrier loss in patients with inflammatory bowel disease. However, the mechanisms that regulate these processes and their relative contributions to disease pathogenesis are not completely understood. We investigated these processes using colitis models in mice. METHODS: We induced colitis by adoptive transfer of CD4(+)CD45RB(hi) cells or administration of dextran sulfate sodium to mice, including those deficient in tumor necrosis factor receptor (TNFR) 1, TNFR2, or the long isoform of myosin light chain kinase (MLCK)...
August 2013: Gastroenterology
Masayuki Nishida, Masaru Yoshida, Shin Nishiumi, Mikio Furuse, Takeshi Azuma
BACKGROUND: Claudins have been demonstrated to be associated with inflammatory bowel disease (IBD), but the specific role of claudin-2 in colorectal inflammation remains undefined. AIMS: We aimed to determine the role of claudin-2 in TNFα-induced colorectal inflammation. METHODS: We used claudin-2 (-/-) mice to assess the role of claudin-2 in colon. The mice were intraperitoneally injected with 3 μg of recombinant murine TNFα, and the NF-κB signaling and mRNA expression levels of proinflammatory cytokines and myosin light chain kinase (MLCK) were evaluated...
June 2013: Digestive Diseases and Sciences
Shila Gilbert, Rongli Zhang, Lee Denson, Richard Moriggl, Kris Steinbrecher, Noah Shroyer, James Lin, Xiaonan Han
Epithelial myosin light chain kinase (MLCK)-dependent barrier dysfunction contributes to the pathogenesis of inflammatory bowel diseases (IBD). We reported that epithelial GM-CSF-STAT5 signalling is essential for intestinal homeostatic response to gut injury. However, mechanism, redundancy by STAT5 or cell types involved remained foggy. We here generated intestinal epithelial cell (IEC)-specific STAT5 knockout mice, these mice exhibited a delayed mucosal wound healing and dysfunctional intestinal barrier characterized by elevated levels of NF-κB activation and MLCK, and a reduction of zonula occludens expression in IECs...
February 2012: EMBO Molecular Medicine
Tamia K Lapointe, Andre G Buret
Compromised epithelial barrier function and tight junction alterations are hallmarks of a number of gastrointestinal disorders, including inflammatory bowel disease (IBD). Increased levels of IL-18 have been observed in mucosal samples from Crohn's disease and ulcerative colitis patients. Remarkably, several reports have demonstrated that immunological or genetic blockage of IL-18 ameliorates the severity of colitis in multiple in vivo models of IBD. Nevertheless, the effects of IL-18 on intestinal epithelial barrier function remain unclear...
February 1, 2012: American Journal of Physiology. Gastrointestinal and Liver Physiology
Anastasia Mashukova, Flavia A Wald, Pedro J Salas
Inflammatory processes disrupt the barrier function in epithelia. Increased permeability often leads to chronic of inflammation. Important among other cytokines, tumor necrosis factor alpha (TNF-α) initiates an NF-κB-mediated response that leads to upregulation of myosin light chain kinase (MLCK), a hallmark of the pathogenesis of inflammatory bowel disease. Here, we found that two components of the evolutionarily conserved organizer of tight junctions and polarity, the polarity complex (atypical protein kinase C [aPKC]-PAR6-PAR3) were downregulated by TNF-α signaling in intestinal epithelial cells and also in vivo during intestinal inflammation...
February 2011: Molecular and Cellular Biology
Christopher R Weber, David R Raleigh, Liping Su, Le Shen, Erika A Sullivan, Yingmin Wang, Jerrold R Turner
Intestinal barrier function is reduced in inflammatory bowel disease (IBD). Tumor necrosis factor (TNF) and interleukin (IL)-13, which are up-regulated in IBD, induce barrier defects that are associated with myosin light chain kinase (MLCK) activation and increased claudin-2 expression, respectively, in cultured intestinal epithelial monolayers. Here we report that these independent signaling pathways have distinct effects on tight junction barrier properties and interact in vivo. MLCK activation alters size selectivity to enhance paracellular flux of uncharged macromolecules without affecting charge selectivity and can be rapidly reversed by MLCK inhibition...
April 16, 2010: Journal of Biological Chemistry
Liping Su, Le Shen, Daniel R Clayburgh, Sam C Nalle, Erika A Sullivan, Jon B Meddings, Clara Abraham, Jerrold R Turner
BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a multifactorial disease thought to be caused by alterations in epithelial function, innate and adaptive immunity, and luminal microbiota. The specific role of epithelial barrier function remains undefined, although increased activity of intestinal epithelial myosin light chain kinase (MLCK), which is the primary mechanism of tumor necrosis factor-induced barrier dysfunction, occurs in human IBD. Our aim was to determine whether, in an intact epithelium, primary dysregulation of the intestinal epithelial barrier by pathophysiologically relevant mechanisms can contribute to development of colitis...
February 2009: Gastroenterology
Yutao Yan, Didier Merlin
Recently, inflammatory bowel disease (IBD) has been the subject of considerable research, with increasing attention being paid to the loss of intestinal epithelial cell barrier function as a mechanism of pathogenesis. Ste20-related proline/alanine-rich kinase (SPAK) is involved in regulating barrier function. SPAK is known to interact with inflammation-related kinases (such as p38, JNK, NKCC1, PKCtheta, WNK and MLCK), and with transcription factor AP-1, resulting in diverse biological phenomena, including cell differentiation, cell transformation and proliferation, cytoskeleton rearrangement, and regulation of chloride transport...
October 28, 2008: World Journal of Gastroenterology: WJG
Linda M Feighery, Sean W Cochrane, Teresa Quinn, Alan W Baird, Daniel O'Toole, Sian-Eleri Owens, Diarmuid O'Donoghue, Randall J Mrsny, David J Brayden
PURPOSE: To examine whether myosin light chain kinase (MLCK) inhibitors can reduce intestinal epithelial permeability increases in vitro. MATERIALS AND METHODS: Isolated rat, mouse and human colonic tissue mucosae and Caco-2 monolayers were exposed to cytochalasin D (cD) and sodium caprate (C10), in the absence and presence of the MLCK inhibitors, ML-9 and D PIK. Transepithelial electrical resistance (TEER) and Papp of [14C]-mannitol or FITC-dextran 4000 (FD-4) were measured...
June 2008: Pharmaceutical Research
Ping-Chang Yang, Shao-Heng He, Peng-Yuan Zheng
BACKGROUND AND AIMS: Intact protein absorption is thought to be a causative factor in several intestinal diseases, such as food allergy, celiac disease and inflammatory bowel disease. However, the mechanism remains unclear. The aim of this study was to characterize a novel signal transduction pathway via which heat stress compromises intestinal epithelial barrier function. METHODS: Heat stress was carried out by exposing confluent human intestinal epithelial cell line T84 cell monolayers to designated temperatures (37-43 degrees C) for 1 h...
November 2007: Journal of Gastroenterology and Hepatology
Brad T Schwarz, Fengjun Wang, Le Shen, Daniel R Clayburgh, Liping Su, Yingmin Wang, Yang-Xin Fu, Jerrold R Turner
BACKGROUND & AIMS: LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells) is a tumor necrosis factor core family member that regulates T-cell activation and causes experimental inflammatory bowel disease. Additional data suggest that LIGHT may be involved in the pathogenesis of human inflammatory bowel disease. The aim of this study was to determine if LIGHT is capable of signaling directly to intestinal epithelia and to define the mechanisms and consequences of such signaling...
June 2007: Gastroenterology
Stephanie A Blair, Sunanda V Kane, Daniel R Clayburgh, Jerrold R Turner
The intestinal epithelial barrier is frequently disrupted in inflammatory bowel disease (IBD) and this has been proposed to play a role in disease pathogenesis and reactivation. In vitro studies show that cytokine-induced epithelial barrier dysfunction can be mediated by increased myosin light chain kinase (MLCK) expression and subsequent myosin II regulatory light chain (MLC) phosphorylation. However, this has never been examined in human disease. The aim of these studies, therefore, was to determine whether MLCK is upregulated in the intestinal epithelium of IBD patients...
February 2006: Laboratory Investigation; a Journal of Technical Methods and Pathology
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