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Infection and Immunity, November 2005, p. 7613-7619, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7613-7619.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Peptidoglycan of Staphylococcus aureus Upregulates Monocyte Expression of CD14, Toll-Like Receptor 2 (TLR2), and TLR4 in Human Blood: Possible Implications for Priming of Lipopolysaccharide Signaling

J. S. Hadley,^1* J. E. Wang,^1,2 S. J. Foster,³ C. Thiemermann,¹ and C. J. Hinds¹

Department of Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, Barts and The London, Queen Mary School of Medicine and Dentistry, London, United Kingdom,¹ Institute for Surgical Research, Rikshospitalet University Hospital, N-0027 Oslo, Norway,² Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom³

Received 15 March 2005/ Returned for modification 30 May 2005/ Accepted 28 July 2005

Previous studies have indicated that peptidoglycan (PepG) from gram-positive bacteria can exert a priming effect on the innate immune response to lipopolysaccharide (LPS) from gram-negative bacteria. Here, we hypothesized that this priming effect may be preceded by enhanced expression of monocyte CD14, Toll-like receptor 2 (TLR2), and TLR4. In an ex vivo whole human blood model, we observed a substantial synergy between LPS and PepG in the release of tumor necrosis factor alpha and interleukin-1ß (IL-1ß) over the 24-h experimental period, whereas the effect on IL-8 and IL-10 release was more time dependent. The priming effect of PepG on cytokine release was preceded by a rapid upregulation of CD14, TLR2, and TLR4 expression on monocytes: at 3 hours there was a twofold increase in CD14 expression (P < 0.03), a fivefold increase in TLR2 expression (P < 0.03), and a twofold increase in TLR4 expression (P < 0.03). CD14 and TLR2 remained upregulated throughout the experimental period following exposure to PepG (P < 0.05). Only a transient upregulation of these monocyte receptors was observed following treatment with LPS or LPS plus PepG. In conclusion, the synergistic effect of LPS and PepG on cytokine release is preceded by a reciprocal upregulation of TLR2 and TLR4 by both bacterial cell wall components.

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* Corresponding author. Mailing address: Department of Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, Barts and The London, Queen Mary School of Medicine and Dentistry, 5th floor, 38 Little Britain, West Smithfield, London EC1A 7BE, United Kingdom. Phone: 44 20 7601 7526. Fax: 44 20 7601 7526. E-mail: julia.hadley{at}btopenworld.com.

Editor: J. L. Flynn

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Infection and Immunity, November 2005, p. 7613-7619, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7613-7619.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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