Intestinal Permeability Regulation by Tight Junction: Implication on Inflammatory Bowel Diseases

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Abstract

Epithelial tight junctions (TJs) are the key structures regulating paracellular trafficking of macromolecules. The TJ is multi-protein complex that forms a selective permeable seal between adjacent epithelial cells and demarcates the boundary between apical and basolateral membrane domains. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, which can act as a trigger for the development of intestinal and systemic diseases. Inflammatory bowel disease (IBD) patients demonstrate increased intestinal paracellular permeability. Although it remains unclear whether barrier dysfunction precedes disease or results from active inflammation, increased intestinal TJ disruption is observed in IBD patients suggest that dysregulation of TJ barrier integrity may predispose or enhance IBD progression. Therefore, therapeutic target to restore the TJ barrier integrity may provide effective therapeutic and preventive approaches against IBD. This review discusses the molecular structure and regulation of intestinal TJs and the involvement of intestinal TJs in IBD pathogenesis.

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Claudin-1 and -2: Novel Integral Membrane Proteins Localizing at Tight Junctions with No Sequence Similarity to Occludin

Mikio Furuse, Kohji Fujita, Takashi Hiiragi … (1998)

Occludin is the only known integral membrane protein localizing at tight junctions (TJ), but recent targeted disruption analysis of the occludin gene indicated the existence of as yet unidentified integral membrane proteins in TJ. We therefore re-examined the isolated junction fraction from chicken liver, from which occludin was first identified. Among numerous components of this fraction, only a broad silver-stained band ∼22 kD was detected with the occludin band through 4 M guanidine-HCl extraction as well as sonication followed by stepwise sucrose density gradient centrifugation. Two distinct peptide sequences were obtained from the lower and upper halves of the broad band, and similarity searches of databases allowed us to isolate two full-length cDNAs encoding related mouse 22-kD proteins consisting of 211 and 230 amino acids, respectively. Hydrophilicity analysis suggested that both bore four transmembrane domains, although they did not show any sequence similarity to occludin. Immunofluorescence and immunoelectron microscopy revealed that both proteins tagged with FLAG or GFP were targeted to and incorporated into the TJ strand itself. We designated them as “claudin-1” and “claudin-2”, respectively. Although the precise structure/function relationship of the claudins to TJ still remains elusive, these findings indicated that multiple integral membrane proteins with four putative transmembrane domains, occludin and claudins, constitute TJ strands.

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Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions

M Furuse, S Tsukita, T. Hirase … (1994)

Occludin is an integral membrane protein localizing at tight junctions (TJ) with four transmembrane domains and a long COOH-terminal cytoplasmic domain (domain E) consisting of 255 amino acids. Immunofluorescence and laser scan microscopy revealed that chick full- length occludin introduced into human and bovine epithelial cells was correctly delivered to and incorporated into preexisting TJ. Further transfection studies with various deletion mutants showed that the domain E, especially its COOH-terminal approximately 150 amino acids (domain E358/504), was necessary for the localization of occludin at TJ. Secondly, domain E was expressed in Escherichia coli as a fusion protein with glutathione-S-transferase, and this fusion protein was shown to be specifically bound to a complex of ZO-1 (220 kD) and ZO-2 (160 kD) among various membrane peripheral proteins. In vitro binding analyses using glutathione-S-transferase fusion proteins of various deletion mutants of domain E narrowed down the sequence necessary for the ZO-1/ZO-2 association into the domain E358/504. Furthermore, this region directly associated with the recombinant ZO-1 produced in E. coli. We concluded that occludin itself can localize at TJ and directly associate with ZO-1. The coincidence of the sequence necessary for the ZO-1 association with that for the TJ localization suggests that the association with underlying cytoskeletons through ZO-1 is required for occludin to be localized at TJ.

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Tight junction proteins.

P Nava, B Agudelo-Jaramillo, A Betanzos … (2002)

A fundamental function of epithelia and endothelia is to separate different compartments within the organism and to regulate the exchange of substances between them. The tight junction (TJ) constitutes the barrier both to the passage of ions and molecules through the paracellular pathway and to the movement of proteins and lipids between the apical and the basolateral domains of the plasma membrane. In recent years more than 40 different proteins have been discovered to be located at the TJs of epithelia, endothelia and myelinated cells. This unprecedented expansion of information has changed our view of TJs from merely a paracellular barrier to a complex structure involved in signaling cascades that control cell growth and differentiation. Both cortical and transmembrane proteins integrate TJs. Among the former are scaffolding proteins containing PDZ domains, tumor suppressors, transcription factors and proteins involved in vesicle transport. To date two components of the TJ filaments have been identified: occludin and claudin. The latter is a protein family with more than 20 members. Both occludin and claudins are integral proteins capable of interacting adhesively with complementary molecules on adjacent cells and of co-polymerizing laterally. These advancements in the knowledge of the molecular structure of TJ support previous physiological models that exhibited TJ as dynamic structures that present distinct permeability and morphological characteristics in different tissues and in response to changing natural, pathological or experimental conditions.

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Author and article information

Journal

Journal ID (nlm-ta): Intest Res

Journal ID (iso-abbrev): Intest Res

Journal ID (publisher-id): IR

Title: Intestinal Research

Publisher: Korean Association for the Study of Intestinal Diseases

ISSN (Print): 1598-9100

ISSN (Electronic): 2288-1956

Publication date (Print): January 2015

Publication date (Electronic): 29 January 2015

Volume: 13

Issue: 1

Pages: 11-18

Affiliations

Institute of Pharmaceutical Research and Development, Wonkwang University College of Pharmacy; BK21plus program & Department of Smart Life-Care Convergence, Wonkwang University Graduate School, Iksan, Korea.

Author notes

Correspondence to Sung Hee Lee, Wonkwang University College of Pharmacy, 460 Iksan-daero, Iksan, Jeollabuk-do 570-749, Korea. Tel: +82-63-850-6820, Fax: +82-63-854-6038, gsseo@ 123456wku.ac.kr

Article

DOI: 10.5217/ir.2015.13.1.11

PMC ID: 4316216

PubMed ID: 25691839

SO-VID: 8d0f3e3e-02ed-4546-8e45-681a8c0399b5

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 18 August 2014

Date revision received : 20 August 2014

Date accepted : 21 August 2014

Funding

Funded by: Wonkwang University

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Intestinal Permeability Regulation by Tight Junction: Implication on Inflammatory Bowel Diseases

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Karger: Gastroenterology

Most cited references 57

Claudin-1 and -2: Novel Integral Membrane Proteins Localizing at Tight Junctions with No Sequence Similarity to Occludin

Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions

Tight junction proteins.

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Cited by 296

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