scholarly journals Chymase-mediated intestinal epithelial permeability is regulated by a protease-activating receptor/matrix metalloproteinase-2-dependent mechanism

2013 ◽  
Vol 304 (5) ◽  
pp. G479-G489 ◽  
Author(s):  
Katherine R. Groschwitz ◽  
David Wu ◽  
Heather Osterfeld ◽  
Richard Ahrens ◽  
Simon P. Hogan
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Barrier Function ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Intestinal Epithelial Barrier ◽  
Epithelial Barrier Function ◽  
Epithelial Barrier Dysfunction

Mast cells regulate intestinal barrier function during disease and homeostasis. Secretion of the mast cell-specific serine protease chymase regulates homeostasis. In the present study, we employ in vitro model systems to delineate the molecular pathways involved in chymase-mediated intestinal epithelial barrier dysfunction. Chymase stimulation of intestinal epithelial (Caco-2 BBe) cell monolayers induced a significant reduction in transepithelial resistance, indicating decreased intestinal epithelial barrier function. The chymase-induced intestinal epithelial barrier dysfunction was characterized by chymase-induced protease-activated receptor (PAR)-2 activation and matrix metalloproteinase (MMP)-2 expression and activation. Consistent with this observation, in vitro analysis revealed chymase-induced PAR-2 activation and increased MAPK activity and MMP-2 expression. Pharmacological and small interfering RNA-mediated antagonism of PAR-2 and MMP-2 significantly attenuated chymase-stimulated barrier dysfunction. Additionally, the chymase/MMP-2-mediated intestinal epithelial dysfunction was associated with a significant reduction in the tight junction protein claudin-5, which was partially restored by MMP-2 inhibition. Finally, incubation of Caco-2 BBe cells with chymase-sufficient, but not chymase-deficient, bone marrow-derived mast cells decreased barrier function, which was attenuated by the chymase inhibitor chymostatin. Collectively, these results suggest that mast cell/chymase-mediated intestinal epithelial barrier function is mediated by PAR-2/MMP-2-dependent pathways.

Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity

2007 ◽  
Vol 293 (3) ◽  
pp. G568-G576 ◽  
Author(s):  
Jie Chen ◽  
Jaladanki N. Rao ◽  
Tongtong Zou ◽  
Lan Liu ◽  
Bernard S. Marasa ◽  
...  
Keyword(s):  
Barrier Function ◽  
Low Dose ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Intestinal Epithelial Barrier ◽  
Tlr2 Expression ◽  
Epithelial Barrier Function ◽  
Cell Functions ◽  
Epithelial Barrier Dysfunction

The Toll-like receptors (TLRs) allow mammalian intestinal epithelium to detect various microbes and activate innate immunity after infection. TLR2 and TLR4 have been identified in intestinal epithelial cells (IECs) as fundamental components of the innate immune response to bacterial pathogens, but the exact mechanism involved in control of TLR expression remains unclear. Polyamines are implicated in a wide variety of biological functions, and regulation of cellular polyamines is a central convergence point for the multiple signaling pathways driving different epithelial cell functions. The current study determined whether polyamines regulate TLR expression, thereby modulating intestinal epithelial barrier function. Depletion of cellular polyamines by inhibiting ornithine decarboxylase (ODC) with α-difluoromethylornithine decreased levels of TLR2 mRNA and protein, whereas increased polyamines by ectopic overexpression of the ODC gene enhanced TLR2 expression. Neither intervention changed basal levels of TLR4. Exposure of normal IECs to low-dose (5 μg/ml) LPS increased ODC enzyme activity and stimulated expression of TLR2 but not TLR4, while polyamine depletion prevented this LPS-induced TLR2 expression. Decreased TLR2 in polyamine-deficient cells was associated with epithelial barrier dysfunction. In contrast, increased TLR2 by the low dose of LPS enhanced epithelial barrier function, which was abolished by inhibition of TLR2 expression with specific, small interfering RNA. These results indicate that polyamines are necessary for TLR2 expression and that polyamine-induced TLR2 activation plays an important role in regulating epithelial barrier function.

scholarly journals Rebeccamycin Attenuates TNF-α-Induced Intestinal Epithelial Barrier Dysfunction by Inhibiting Myosin Light Chain Kinase Production

2017 ◽  
Vol 41 (5) ◽  
pp. 1924-1934 ◽  
Author(s):  
Akihiro Watari ◽  
Yuta Sakamoto ◽  
Kota Hisaie ◽  
Kazuki Iwamoto ◽  
Miho Fueta ◽  
...  
Keyword(s):  
Barrier Function ◽  
Myosin Light Chain ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Intestinal Epithelial Barrier ◽  
Epithelial Barrier Function ◽  
Cell Monolayers ◽  
Tnf Α ◽  
Epithelial Barrier Dysfunction

Background/Aims: Although proinflammatory cytokine–induced disruption of intestinal epithelial barrier integrity is associated with intestinal inflammatory disease, effective treatment for barrier dysfunction is lacking. Previously, we demonstrated that rebeccamycin alleviates epithelial barrier dysfunction induced by inflammatory cytokines in Caco-2 cell monolayers; however, the underlying mechanism remained unclear. Here, we investigated the mechanism by which rebeccamycin protects the epithelial barrier function of Caco-2 cells exposed to TNF-α. Methods: To confirm the epithelial barrier function of Caco-2 cell monolayers, transepithelial electrical resistance (TER) and paracellular permeability were measured. Production levels and localization of tight junction (TJ) proteins were analyzed by immunoblot and immunofluorescence, respectively. Phosphorylated myosin light chain (pMLC) and MLC kinase (MLCK) mRNA expression levels were determined by immunoblot and quantitative RT-PCR, respectively. Results: Rebeccamycin attenuated the TNF-α-induced reduction in TER and increase in paracellular permeability. Rebeccamycin increased claudin-5 expression, but not claudin-1, -2, -4, occludin or ZO-1 expression, and prevented the TNF-α-induced changes in ZO-1 and occludin localization. Rebeccamycin suppressed the TNF-α-induced increase in MLCK mRNA expression, thus suppressing MLC phosphorylation. The rebeccamycin-mediated reduction in MLCK production and protection of epithelial barrier function were alleviated by Chk1 inhibition. Conclusion: Rebeccamycin attenuates TNF-α-induced disruption of intestinal epithelial barrier integrity by inducing claudin-5 expression and suppressing MLCK production via Chk1 activation.

scholarly journals Intestinal Epithelial Barrier Dysfunction in Food Hypersensitivity

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Linda Chia-Hui Yu
Keyword(s):  
Mast Cell ◽  
Cell Surface ◽  
Critical Role ◽  
Mast Cell Activation ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Intestinal Epithelial Barrier ◽  
Food Antigens ◽  
Epithelial Barrier Dysfunction

Intestinal epithelial barrier plays a critical role in the maintenance of gut homeostasis by limiting the penetration of luminal bacteria and dietary allergens, yet allowing antigen sampling for the generation of tolerance. Undigested proteins normally do not gain access to the lamina propria due to physical exclusion by tight junctions at the cell-cell contact sites and intracellular degradation by lysosomal enzymes in enterocytes. An intriguing question then arises: how do macromolecular food antigens cross the epithelial barrier? This review discusses the epithelial barrier dysfunction in sensitized intestine with special emphasis on the molecular mechanism of the enhanced transcytotic rates of allergens. The sensitization phase of allergy is characterized by antigen-induced cross-linking of IgE bound to high affinity FcεRI on mast cell surface, leading to anaphylactic responses. Recent studies have demonstrated that prior to mast cell activation, food allergens are transported in large quantity across the epithelium and are protected from lysosomal degradation by binding to cell surface IgE and low-affinity receptor CD23/FcεRII. Improved immunotherapies are currently under study including anti-IgE and anti-CD23 antibodies for the management of atopic disorders.

scholarly journals The role of secreted Hsp90α in HDM-induced asthmatic airway epithelial barrier dysfunction

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Cuiping Ye ◽  
Chaowen Huang ◽  
Mengchen Zou ◽  
Yahui Hu ◽  
Lishan Luo ◽  
...  
Keyword(s):  
Barrier Function ◽  
Epithelial Barrier ◽  
Airway Epithelial ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Function ◽  
Asthmatic Airway ◽  
Epithelial Barrier Dysfunction

Abstract Background The dysfunction of airway epithelial barrier is closely related to the pathogenesis of asthma. Secreted Hsp90α participates in inflammation and Hsp90 inhibitor protects endothelial dysfunction. In the current study, we aimed to explore the role of secreted Hsp90α in asthmatic airway epithelial barrier function. Methods Male BALB/c mice were sensitized and challenged with HDM to generate asthma model. The 16HBE and Hsp90α-knockdown cells were cultured and treated according to the experiment requirements. Transepithelial Electric Resistance (TEER) and permeability of epithelial layer in vitro, distribution and expression of junction proteins both in vivo and in vitro were used to evaluate the epithelial barrier function. Western Blot was used to evaluate the expression of junction proteins and phosphorylated AKT in cells and lung tissues while ELISA were used to evaluate the Hsp90α expression and cytokines release in the lung homogenate. Results HDM resulted in a dysfunction of airway epithelial barrier both in vivo and in vitro, paralleled with the increased expression and release of Hsp90α. All of which were rescued in Hsp90α-knockdown cells or co-administration of 1G6-D7. Furthermore, either 1G6-D7 or PI3K inhibitor LY294002 suppressed the significant phosphorylation of AKT, which caused by secreted and recombinant Hsp90α, resulting in the restoration of epithelial barrier function. Conclusions Secreted Hsp90α medicates HDM-induced asthmatic airway epithelial barrier dysfunction via PI3K/AKT pathway, indicating that anti-secreted Hsp90α therapy might be a potential treatment to asthma in future.

cis 9, trans 11, but not trans 10, cis 12 CLA isomer, impairs intestinal epithelial barrier function in IPEC-J2 cells and mice through activation of GPR120-[Ca2+]i and the MLCK signaling pathway

2020 ◽  
Vol 11 (4) ◽  
pp. 3657-3667
Author(s):  
Han Su ◽  
Weijie Zhao ◽  
Fenglin Zhang ◽  
Min Song ◽  
Fangfang Liu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Barrier Function ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Epithelial Barrier Function

In vitro and in vivo studies show that c9, t11-CLA, but not t10, c12-CLA isomer, impairs intestinal epithelial barrier function in IPEC-J2 cells and mice via activation of GPR120-[Ca2+]i and the MLCK pathway.

Collagen peptides ameliorate intestinal epithelial barrier dysfunction in immunostimulatory Caco-2 cell monolayers via enhancing tight junctions

2017 ◽  
Vol 8 (3) ◽  
pp. 1144-1151 ◽  
Author(s):  
Qianru Chen ◽  
Oliver Chen ◽  
Isabela M. Martins ◽  
Hu Hou ◽  
Xue Zhao ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Intestinal Epithelial Barrier ◽  
Cell Monolayers ◽  
Collagen Peptides ◽  
Epithelial Barrier Dysfunction

Alaska pollock skin derived collagen peptides could be considered as dietary supplements for intestinal barrier function promotion and associated diseases.

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