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Infection and Immunity, May 2000, p. 2907-2915, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Inducible Expression of Human beta -Defensin 2 by Fusobacterium nucleatum in Oral Epithelial Cells: Multiple Signaling Pathways and Role of Commensal Bacteria in Innate Immunity and the Epithelial Barrier

Suttichai Krisanaprakornkit,1 Janet R. Kimball,1 Aaron Weinberg,2 Richard P. Darveau,3 Brian W. Bainbridge,3 and Beverly A. Dale1,3,4,*

Department of Oral Biology1 and Department of Periodontics,3 School of Dentistry, and Departments of Biochemistry and Medicine/Dermatology, School of Medicine,4 University of Washington, Seattle, Washington 98195, and Departments of Periodontics and Microbiology, School of Dentistry, Case Western Reserve University, Cleveland, Ohio 441062

Received 16 November 1999/Returned for modification 21 January 2000/Accepted 7 February 2000

Human gingival epithelial cells (HGE) express two antimicrobial peptides of the beta -defensin family, human beta -defensin 1 (hBD-1) and hBD-2, as well as cytokines and chemokines that contribute to innate immunity. In the present study, the expression and transcriptional regulation of hBD-2 was examined. HBD-2 mRNA was induced by cell wall extract of Fusobacterium nucleatum, an oral commensal microorganism, but not by that of Porphyromonas gingivalis, a periodontal pathogen. HBD-2 mRNA was also induced by the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha ) and phorbol myristate acetate (PMA), an epithelial cell activator. HBD-2 mRNA was also expressed in 14 of 15 noninflamed gingival tissue samples. HBD-2 peptide was detected by immunofluorescence in HGE stimulated with F. nucleatum cell wall, consistent with induction of the mRNA by this stimulant. Kinetic analysis indicates involvement of multiple distinct signaling pathways in the regulation of hBD-2 mRNA; TNF-alpha and F. nucleatum cell wall induced hBD-2 mRNA rapidly (2 to 4 h), while PMA stimulation was slower (~10 h). In contrast, each stimulant induced interleukin 8 (IL-8) within 1 h. The role of TNF-alpha as an intermediary in F. nucleatum signaling was ruled out by addition of anti-TNF-alpha that did not inhibit hBD-2 induction. However, inhibitor studies show that F. nucleatum stimulation of hBD-2 mRNA requires both new gene transcription and new protein synthesis. Bacterial lipopolysaccharides isolated from Escherichia coli and F. nucleatum were poor stimulants of hBD-2, although they up-regulated IL-8 mRNA. Collectively, our findings show inducible expression of hBD-2 mRNA via multiple pathways in HGE in a pattern that is distinct from that of IL-8 expression. We suggest that different aspects of innate immune responses are differentially regulated and that commensal organisms have a role in stimulating mucosal epithelial cells in maintaining the barrier that contributes to homeostasis and host defense.

* Corresponding author. Mailing address: Department of Oral Biology, Room #B147, Box 357132, University of Washington, Seattle, WA 98195-7132. Phone: (206) 543-4393. Fax: (206) 685-3162. E-mail: bdale{at}u.washington.edu.

Infection and Immunity, May 2000, p. 2907-2915, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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