title: Antibiotic-induced cell wall fragments of Staphylococcus aureus increase endothelial chemokine secretion and adhesiveness for granulocytes.
abstract: 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.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: van Langevelde
authors.forename: E
authors.initials: E
authors.lastname: Ravensbergen
authors.forename: P
authors.initials: P
authors.lastname: Grashoff
authors.forename: H
authors.initials: H
authors.lastname: Beekhuizen
authors.forename: P H
authors.initials: PH
authors.lastname: Groeneveld
authors.forename: J T
authors.initials: JT
authors.lastname: van Dissel
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal; D002448:Cell Adhesion / Q000187:drug effects; D002473:Cell Wall / Q000737:chemistry* / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018925:Chemokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006098:Granulocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000187:drug effects / Q000648:ultrastructure*
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D018925:Chemokines; D016209:Interleukin-8; D011453:Prostaglandins; D018799:Intercellular Adhesion Molecule-1