title: Irsogladine maleate regulates neutrophil migration and E-cadherin expression in gingival epithelium stimulated by Aggregatibacter actinomycetemcomitans.
abstract: Irsogladine maleate (IM) counters Aggregatibacter actinomycetemcomitans-induced reduction of the gap junction intercellular communication and the expression of zonula occludens-1, which is a major tight junction structured protein, in cultured human gingival epithelial cells (HGEC). In addition, IM obviates the A. actinomycetemcomitans-induced increase in interleukin (IL)-8 levels in HGEC. Thus, by regulating the intercellular junctional complex and chemokine secretion in HGEC, IM may be useful to prevent periodontal disease. To clarify the effects and regulatory mechanism of IM in vivo and in vitro, we examined the expression of E-cadherin and neutrophil chemotaxis induced by A. actinomycetemcomitans under IM pretreatment. Immunohistochemical studies revealed that A. actinomycetemcomitans application to the gingival sulcus decreased the number of cells positive for E-cadherin and increased those positive for cytokine-induced neutrophil chemoattractant-2alpha (CINC-2alpha) in rat gingival epithelium. However, in IM-pretreated rats, A. actinomycetemcomitans application had little effect on CINC-2alpha and E-cadherin in gingival epithelium. In cultured HGEC, real-time PCR and Western blotting showed that IM and the ERK inhibitor PD98059 abolished the A. actinomycetemcomitans-induced increase in CXCL-1 and IL-8 in HGEC. On the other hand, IM, PD98059, and the p38 MAP kinase inhibitor SB203580 recovered the decrease in E-cadherin expression. In addition, conditioned medium from A. actinomycetemcomitans-stimulated HGEC enhanced human neutrophil chemotaxis, compared to that from un-stimulated HGEC or that from A. actinomycetemcomitans-stimulated HGEC under IM pretreatment. Furthermore, IM down-regulated the p38 MAP kinase and ERK phosphorylations induced by A. actinomycetemcomitans. In conclusion, IM may control A. actinomycetemcomitans-induced gingival inflammation by regulating neutrophil migration and E-cadherin expression in gingival epithelium.
authors.affiliation: Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical Sciences, Minami-ku, Japan. tfuji@hiroshima-u.ac.jp
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fujita
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kishimoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Shiba
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hayashida
authors.forename: Mikihito
authors.initials: M
authors.lastname: Kajiya
authors.forename: Yuushi
authors.initials: Y
authors.lastname: Uchida
authors.forename: Shinji
authors.initials: S
authors.lastname: Matsuda
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Takeda
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Ouhara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Abiko
authors.forename: Hidemi
authors.initials: H
authors.lastname: Kurihara
mesh_terms: D000199:Actins / Q000502:physiology; D016976:Aggregatibacter actinomycetemcomitans / Q000502:physiology*; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis* / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium; D005881:Gingiva / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D015151:Immunoblotting; D016209:Interleukin-8 / Q000502:physiology; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011916:Rats, Inbred F344; D014227:Triazines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D015820:Cadherins; D054360:Chemokine CXCL1; D016209:Interleukin-8; D014227:Triazines; D048051:p38 Mitogen-Activated Protein Kinases; C041836:irsogladine