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Antimicrobial Agents and Chemotherapy, December 1999, p. 2984-2989, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Antibiotic-Induced Cell Wall Fragments of Staphylococcus aureus Increase Endothelial Chemokine Secretion and Adhesiveness for Granulocytes

P. van Langevelde, E. Ravensbergen, P. Grashoff, H. Beekhuizen, P. H. P. Groeneveld, and J. T. van Dissel*

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

Received 21 May 1998/Returned for modification 6 August 1998/Accepted 2 October 1999

Antibiotics release inflammatory fragments, such as lipoteichoic acid (LTA) and peptidoglycan (PG), from the cell wall of Staphylococcus aureus. In this study, we exposed S. aureus cultures to a number of beta -lactam antibiotics (imipenem, flucloxacillin, and cefamandole) and protein synthesis-inhibiting antibiotics (erythromycin, clindamycin, and gentamicin) and investigated whether supernatants of these cultures differ in their capacity to stimulate endothelial cells (EC). After 24 h of incubation, endothelial adhesiveness for leukocytes, surface expression of various adhesion molecules, and secretion of the chemokines interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) were measured. Supernatants of beta -lactam-exposed cultures (designated beta -lactam supernatants) enhanced the adhesiveness of EC for granulocytes, whereas those of protein synthesis-inhibiting antibiotic-exposed cultures (designated protein synthesis-inhibitor supernatants) did not. This hyperadhesiveness coincided with a higher intercellular adhesion molecule-1 expression on the surface of the stimulated EC. In addition, EC stimulated with beta -lactam supernatants secreted significantly higher concentrations of the chemokines IL-8 and MCP-1 than those stimulated with protein synthesis-inhibitor supernatants. The finding that the concentrations of LTA and PG in beta -lactam supernatants were much higher than those in protein synthesis-inhibitor supernatants suggests that the observed differences in stimulatory effect between these supernatants are a result of differences in the release of cell wall fragments, although the presence of other stimulatory factors in the supernatants cannot be excluded. In conclusion, our results argue for a release of LTA and PG from S. aureus after exposure to beta -lactam antibiotics that enhances the development of a systemic inflammatory response by stimulating EC such that adhesiveness for granulocytes is increased and large amounts of IL-8 and MCP-1 are secreted.

* Corresponding author. Mailing address: Department of Infectious Diseases, C5-P, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31-71-5262613. Fax: 31-71-5266758. E-mail: jtvandissel{at}infectdis.azl.nl.

Antimicrobial Agents and Chemotherapy, December 1999, p. 2984-2989, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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