Irsogladine maleate regulates epithelial barrier function in tumor necrosis factor-α-stimulated human gingival epithelial cellsby T. Fujita, H. Yumoto, H. Shiba, K. Ouhara, T. Miyagawa, T. Nagahara, S. Matsuda, H. Kawaguchi, T. Matsuo, S. Murakami, H. Kurihara

Journal of Periodontal Research

About

Year
2011
DOI
10.1111/j.1600-0765.2011.01404.x
Subject
Periodontics

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Text

Irsogladine maleate regulates epithelial barrier function in tumor necrosis factor-a-stimulated human gingival epithelial cells

T. Fujita1, H. Yumoto2, H. Shiba1,

K. Ouhara1, T. Miyagawa1,

T. Nagahara1, S. Matsuda1,

H. Kawaguchi1, T. Matsuo2,

S. Murakami3, H. Kurihara1 1Department of Periodontal Medicine, Division of

Frontier Medical Science, Hiroshima University

Graduate School of Biomedical Sciences,

Hiroshima, Japan, 2Department of Conservative

Dentistry, Institute of Health Biosciences, The

University of Tokushima Graduate School,

Tokushima, Japan and 3Department of

Periodontology, Division of Oral Biology and

Disease Control, Osaka University Graduate

School of Dentistry, Osaka, Japan

Periodontitis is an inflammatory condition caused by the colonization of periodontopathogenic bacteria, such as

Porphyromonas gingivalis or Aggregatibacter actinomycetemcomitans, in the gingival sulcus. The gingival junctional epithelium is located at a strategically important interface at the bottom of the gingival sulcus and contributes actively to inflammatory processes because it represents the first line of defense against microbial attack (1–3).

As epithelial cells function as a mechanical barrier (4,5), disruption of the gingival epithelial cell layer allows periodontopathogenic bacteria to invade periodontal tissue, leading to periodontal disease. Therefore, regulation of the barrier function may prevent bacterial invasion.

Although epithelial cells are generally interconnected by tight junctions, adherence junctions, desmosomes and gap junctions, previous studies have shown that the junctional epithelium is interconnected only by a few desmosomes, and occasionally by gap junctions, and has wide intercellular spaces (1,2). However, we recently found that claudin-1, a tight junction

Fujita T, Yumoto H, Shiba H, Ouhara K, Miyagawa T, Nagahara T, Matsuda S,

Kawaguchi H, Matsuo T, Murakami S, Kurihara H. Irsogladine maleate regulates epithelial barrier function in tumor necrosis factor-a-stimulated human gingival epithelial cells. J Periodont Res 2012; 47: 55–61.  2011 John Wiley & Sons A/S

Background and Objective: As epithelial cells function as a mechanical barrier, the permeability of the gingival epithelial cell layer indicates a defensive capability against invasion by periodontal pathogens. We have reported the expression of claudin-1 and E-cadherin, key regulators of permeability, in the gingival junctional epithelium. Irsogladine maleate (IM) is a medication for gastric ulcers and also regulates Aggregatibacter actinomycetemcomitans-stimuated chemokine secretion and E-cadherin expression in gingival epithelium. In this study, we have further investigated the effects of IM on the barrier functions of gingival epithelial cells under inflammatory conditions.

Material and Methods: We examined the permeability, and the expression of claudin-1 and E-cadherin, in human gingival epithelial cells (HGECs) stimulated with tumor necrosis factor (TNF)-a, with or without IM.

Results: TNF-a increased the permeability of HGECs, and IM abolished the increase. TNF-a reduced the expression of E-cadherin in HGECs, and IM reversed the reduction. In addition, immunofluorescence staining showed that TNF-a disrupted claudin-1 expression in HGECs, and IM reversed this effect.

Conclusion: The results suggest that IM reverses the TNF-a-induced disruption of the gingival epithelial barrier by regulating E-cadherin and claudin-1.

Tsuyoshi Fujita, Department of Periodontal

Medicine, Division of Frontier Medical Science,

Hiroshima University Graduate School of

Biomedical Sciences, 1-2-3, Kasumi, Minami-ku,

Hiroshima 734-8553, Japan

Tel: +81 82 257 5663

Fax: +81 82 257 5664 e-mail: tfuji@hiroshima-u.ac.jp

Key words: claudin-1; E-cadherin; epithelial barrier; irsogladine maleate; tumor necrosis factor-a

Accepted for publication July 5, 2011

J Periodont Res 2012; 47: 55–61

All rights reserved  2011 John Wiley & Sons A/S

JOURNAL OF PERIODONTAL RESEARCH doi:10.1111/j.1600-0765.2011.01404.x structured protein, was expressed in the healthy junctional epithelium of Fischer 344 rats (6). A previous report showed that claudin-1-deficient mice died within 1 d of birth and exhibited severe defects in the permeability of the epidermis (7). Cells over-expressing claudin-1 showed increased transepithelial electrical resistance (8). Therefore, claudin-1 may play an important role in the barrier function of the junctional epithelium, in spite of the absence of tight junctions. E-cadherin, a key protein involved in the formation of desmosomes and adherens junctions, is known to regulate the permeability of epithelial cells (5,9). In the gastric mucosal epithelium, the disruption of

E-cadherin seems to cause epithelial permeability to increase (10). Immunohistochemical staining has shown that

E-cadherin is expressed in the healthy junctional epithelium of humans and rats (6,11) and that its level is decreased in diseased tissue (11,12). Therefore,

E-cadherin plays an important role against bacterial invasion in the gingival junctional epithelium.

Irsogladine maleate (IM) is known to enhance gap junctional intercellular communication in cultured rabbit gastric epithelial and pancreatic cancer cells (13,14), and is used clinically as an anti-gastric ulcer agent. Our previous study showed that IM inhibits

A. actinomycetemcomitans-induced inflammatory responses in the gingival epithelium by suppressing neutrophil migration in vivo and in vitro (12). In addition, IM rescued the A. actinomycetemcomitans-induced reduction in

E-cadherin in vivo and in vitro (12).

Furthermore, IM countered the reduction of gap junctional intercellular communication in cultures of human gingival epithelial cells (HGECs) stimulated with A. actinomycetemcomitans or interleukin (IL)-1b (15,16). As IM seems to regulate the inflammatory responses induced by bacterial attack and cytokine stimulation in the human gingival epithelium, it may be a candidate preventive medicine for periodontal disease.