Neutralization of IL-6 and TNF-α ameliorates intestinal permeability in DSS-induced colitis

Xiao, Yongtao; Yan, Wei; Cao, Yi; Yan, Junkai; Cai, Wei

doi:10.1016/j.cyto.2016.04.012

Cited by 148 publications

(99 citation statements)

References 18 publications

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“…Numerous previous studies, including those by our group, have confirmed that inflammatory cytokine-mediated intestinal epithelial barrier dysfunction contributes to multiple enteropathies, including IBD (31–34); such cytokines disrupt the integrity of the TJ complex and increase intestinal barrier permeability. A study by Chen et al showed that stimulating Caco-2 monolayers with 10 ng/ml TNF-α did not affect TJ protein expression levels but that TNF-α played a role in altering the distribution of TJ proteins (35).…”

Section: Discussionsupporting

confidence: 60%

AGR2 ameliorates tumor necrosis factor-α-induced epithelial barrier dysfunction via suppression of NF-κB p65-mediated MLCK/p-MLC pathway activation

Sun

2017

International Journal of Molecular Medicine

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Intestinal epithelial barrier dysfunction plays a critical role in the pathogenesis of inflammatory bowel disease (IBD). Anterior gradient protein 2 homologue (AGR2) assists in maintaining intestinal homeostasis in dextran sulphate sodium-induced mouse ileocolitis; however, it is unclear whether it modulates intestinal barrier function. Our study aimed to investigate the protective role of AGR2 in tumor necrosis factor (TNF)-α-induced intestinal epithelial barrier injury. Caco-2 cell monolayers were pre-transfected with an AGR2 plasmid and then exposed to TNF-α. Epithelial permeability was assessed by detecting transepithelial electrical resistance and fluorescein isothiocyanate-dextran (40 kDa) flux. The protein expression levels of zonula occludens-1 (ZO-1), occludin, claudin-1, myosin light chain kinase (MLCK)/p-MLC, and nuclear factor (NF)-κB p65 were determined by western blotting. In addition, the cellular distributions of ZO-1, occludin, F-actin, and NF-κB p65 were evaluated by immunofluorescence staining. The results showed that the AGR2 mRNA and protein expression levels were both decreased in the Caco-2 cell monolayers, while AGR2 overexpression significantly ameliorated TNF-α-induced epithelial barrier hyperpermeability, increased the expression of tight junction (TJ) proteins and stabilized the cytoskeletal structure. Furthermore, AGR2 inhibited the changes in MLCK, MLC and p-MLC expression in response to TNF-α stimulation. Collectively, our study suggests that AGR2 inhibits TNF-α-induced Caco-2 cell hyperpermeability by regulating TJ and that this protective mechanism may be promoted by inhibition of NF-κB p65-mediated activation of the MLCK/p-MLC signaling pathway.

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Section: Discussionsupporting

confidence: 60%

AGR2 ameliorates tumor necrosis factor-α-induced epithelial barrier dysfunction via suppression of NF-κB p65-mediated MLCK/p-MLC pathway activation

Sun

2017

International Journal of Molecular Medicine

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“…induces barrier dysfunction in the setting of intestinal inflammation, and neutralization of IL-6 prevents intestinal hyperpermeability and MLCK expression in a mouse model of colitis (53). Our finding that IL-6 was lower in the blood and peritoneal fluid of MLCK -/-mice therefore represents a potential mechanism through which permeability could be reduced, by preventing the feed-forward worsening of barrier function induced by proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 70%

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

Lorentz

Liang

Meng

et al. 2017

Mol Med

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Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the perijunctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK -/-and wild-type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK -/-mice (95% versus 24%, p < 0.0001). Intestinal permeability increased in septic WT mice compared with unmanipulated mice. In contrast, permeability in septic MLCK -/-mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK -/-mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8 and 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion, as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK -/-mice; however, survival was similar between septic MLCK -/-mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

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“…36 Briefly, the slides were incubated with xylol and descending concentrations of ethanol. Endogenous peroxidases were blocked by using 0.3% H 2 O 2 for 10 min at RT.…”

Section: Methodsmentioning

confidence: 99%

Downregulated expression of microRNA-124 in pediatric intestinal failure patients modulates macrophages activation by inhibiting STAT3 and AChE

et al. 2016

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Intestinal inflammation plays a critical role in the pathogenesis of intestinal failure (IF). The macrophages are essential to maintain the intestinal homeostasis. However, the underlying mechanisms of intestinal macrophages activation remain poorly understood. Since microRNAs (miRNAs) have pivotal roles in regulation of immune responses, here we aimed to investigate the role of miR-124 in the activation of intestinal macrophages. In this study, we showed that the intestinal macrophages increased in pediatric IF patients and resulted in the induction of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The miRNA fluorescence in situ hybridization analysis showed that the expression of miR-124 significantly reduced in intestinal macrophages in IF patients. Overexpression of miR-124 was sufficient to inhibit intestinal macrophages activation by attenuating production of IL-6 and TNF-α. Further studies showed that miR-124 could directly target the 3′-untranslated region of both signal transducer and activator of transcription 3 (STAT3) and acetylcholinesterase (AChE) mRNAs, and suppress their protein expressions. The AChE potentially negates the cholinergic anti-inflammatory signal by hydrolyzing the acetylcholine. We here showed that intestinal macrophages increasingly expressed the AChE and STAT3 in IF patients when compared with controls. The inhibitors against to STAT3 and AChE significantly suppressed the lipopolysaccharides-induced IL-6 and TNF-α production in macrophages. Taken together, these findings highlight an important role for miR-124 in the regulation of intestinal macrophages activation, and suggest a potential application of miR-124 in pediatric IF treatment regarding as suppressing intestinal inflammation.

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Neutralization of IL-6 and TNF-α ameliorates intestinal permeability in DSS-induced colitis

Cited by 148 publications

References 18 publications

AGR2 ameliorates tumor necrosis factor-α-induced epithelial barrier dysfunction via suppression of NF-κB p65-mediated MLCK/p-MLC pathway activation

AGR2 ameliorates tumor necrosis factor-α-induced epithelial barrier dysfunction via suppression of NF-κB p65-mediated MLCK/p-MLC pathway activation

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

Downregulated expression of microRNA-124 in pediatric intestinal failure patients modulates macrophages activation by inhibiting STAT3 and AChE

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