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Infection and Immunity, September 2006, p. 5211-5220, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00056-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Actinobacillus actinomycetemcomitans Outer Membrane Protein 100 Triggers Innate Immunity and Production of ß-Defensin and the 18-Kilodalton Cationic Antimicrobial Protein through the Fibronectin-Integrin Pathway in Human Gingival Epithelial Cells

Department of Bacteriology,¹ and Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan,² Department of Immunology, The Forsyth Institute, Boston, Massachusetts 02115-3799,³ Department of Dermatology, Ehime University School of Medicine, Onsen-gun, Ehime 791-0295, Japan⁴

Received 11 January 2006/ Returned for modification 30 March 2006/ Accepted 30 May 2006

Antimicrobial peptides, human ß-defensin (hBD), and the 18-kDa cationic antimicrobial protein (CAP18) are components of innate immunity. These peptides have antimicrobial activity against bacteria, fungi, and viruses. Actinobacillus actinomycetemcomitans is a gram-negative facultative anaerobe implicated in the initiation of periodontitis. The innate immunity peptides have antibacterial activity against A. actinomycetemcomitans. We investigated the molecular mechanism of human gingival epithelial cells (HGEC) responding to exposure to A. actinomycetemcomitans. HGEC constitutively express hBD1 and inducibly express hBD2, hBD3, and CAP18 on exposure to A. actinomycetemcomitans. The level of expression varies among clinical isolates. In the signaling pathway for hBD2 induction by the bacterial contact, we demonstrate that the mitogen-activated protein (MAP) kinase and not the NF-B transcription factor pathway is used. We found the outer membrane protein 100 (Omp100; identified by molecular mass) is the component inducing the hBD2 response. Omp100 binds to fibronectin, an extracellular matrix inducing hBD2 via the MAP kinase pathway. Anti-integrin ₅ß₁, antifibronectin, genistein, and PP2 suppress the Omp100-induced expression of hBD2, suggesting that Src kinase is involved through integrin ₅ß₁. The inflammatory cytokines, tumor necrosis factor (TNF-), interleukin-1ß (IL-1ß), IL-6 and IL-8, produced by HGEC on contact with A. actinomycetemcomitans also stimulate expression of hBD2. Further, neutralizing antibody against TNF- or IL-8 partially inhibits the induction of hBD2 on bacterial contact. Therefore, we found that the induction of the antimicrobial peptides is mediated by a direct response principally through an Omp100-fibronectin interaction, and using secondary stimulation by inflammatory cytokines induced by the bacterial exposure.

Editor: F. C. Fang

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