Oral epithelia serve as a first line of defense for oral and periodontal health via innate host defense mechanisms. Human gingival epithelial cells (HGECs) express two antimicrobial peptides of the beta-defensin family, human beta-defensin-1 (hBD-1) and -2 (hBD-2) that contribute to innate immune responses. The potential importance of these peptides in oral health and disease susceptibility is only recently beginning to be appreciated. Production of hBD-1 and hBD-2 is stimulated when HGECs are exposed to an oral commensal bacterium, Fusobacterium nucleatum. HBD-1 mRNA is also up regulated by exposure to TNFalpha, an inflammatory mediator, while hBD-1 mRNA is constitutively expressed. These preliminary studies suggest that commensal organisms may be important in maintaining the normal protective barrier function of the oral mucosa in vivo by partial activation of the innate immune system. Several findings or hypotheses are the focus of this project: 1) that expression of beta-defensins is associated with differentiation in oral mucosa; 2) that beta-defensins are regulated by known or novel cell surface receptors, possibly including CD14 and TLRs, 3) that signal transduction via the transcription factor NF kB is critical for hBD-2 mRNA expression, 4) that the pathway for stimulation may differ from that of other host innate immune responses, such as the chemokine IL-8, 5) that new gene expression may be required. The present proposal uses cell and molecular studies to investigate the regulation of expression of beta-defensins in relation to epithelial differentiation, and to identify cell surface receptors and signaling pathways responsible for their expression in response to the oral commensal organism, F. nucleatum. Understanding the signaling pathways and means to enhance peptide expression will have future potential for enhancing antimicrobial peptide expression for prevention and treatment of oral microbial disorders, including periodontal disease, caries, recurrent candidal infections, and oral mucositis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013573-02
Application #
6379979
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Lunsford, Dwayne
Project Start
2000-07-15
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$258,400
Indirect Cost
Name
University of Washington
Department
Dentistry
Type
Schools of Dentistry
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Yin, Lei; Chino, Takahiro; Horst, Orapin V et al. (2010) Differential and coordinated expression of defensins and cytokines by gingival epithelial cells and dendritic cells in response to oral bacteria. BMC Immunol 11:37
Nittayananta, Wipawee; Hladik, Florian; Klausner, Mitchell et al. (2009) HIV type 1 fails to trigger innate immune factor synthesis in differentiated oral epithelium. AIDS Res Hum Retroviruses 25:1013-21
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Kimball, Janet R; Nittayananta, Wipawee; Klausner, Mitchell et al. (2006) Antimicrobial barrier of an in vitro oral epithelial model. Arch Oral Biol 51:775-83

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