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Infection and Immunity, December 2006, p. 6847-6854, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00389-06

Signal Transduction and Nuclear Responses in Staphylococcus aureus- Induced Expression of Human ß-Defensin 3 in Skin Keratinocytes{triangledown}

Barbara E. Menzies1,2* and Aimee Kenoyer1

Medical Research Service of the Veterans Affairs/Puget Sound Health Care System, Seattle, Washington,1 Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington2

Received 10 March 2006/ Returned for modification 23 March 2006/ Accepted 24 August 2006

The human ß-defensin 3 (hBD-3) is an inducible epithelial peptide antibiotic that has potent antistaphylococcal activity. Infection of skin epithelial cells with viable Staphylococcus aureus, a common skin pathogen, induces increased gene expression of hBD-3 and other antimicrobial peptides. The aim of this study was to identify signaling pathways and nuclear responses that contribute to the gene expression of hBD-3 in primary human keratinocytes upon contact with S. aureus. Increased hBD-3 peptide was observed by immunofluorescence microscopy in keratinocytes exposed to S. aureus and to lipoteichoic acid (LTA). Both are ligands for the cell surface Toll-like receptor 2 (TLR2), and thus the contribution of TLR2 signaling in hBD-3 expression was examined. Functional inhibition of TLR2 prior to S. aureus stimulation significantly decreased hBD-3 mRNA levels by 37%, attesting to the involvement of this surface receptor in the initial recognition and downstream signaling for hBD-3 expression. Treatment of keratinocytes with a p38 mitogen-activated protein kinase (MAPK) inhibitor prior to either S. aureus or LTA stimulation was associated with reduced hBD-3 mRNA transcripts and peptide. We also propose a role for the MAPK-regulated transcriptional activating protein 1 in S. aureus-induced hBD-3 gene expression. Combined, these studies indicate a role for TLR2 signaling and MAPK activation in the upregulation of hBD-3 and demonstrate the innate immune capacity of skin keratinocytes under conditions of S. aureus challenge to enhance the local expression of this antistaphylococcal peptide antibiotic.

* Corresponding author. Mailing address: Department of Veterans Affairs, S-111-ID, 1660 S. Columbian Way, Puget Sound Health Care System, Seattle, WA 98108. Phone: (206) 277-4576. Fax: (206) 764-2689. E-mail: bmenzies{at}u.washington.edu.

{triangledown} Published ahead of print on 5 September 2006.

Editor: J. N. Weiser

Infection and Immunity, December 2006, p. 6847-6854, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00389-06




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