Differential modulation of the induction of inflammatory mediators by antibiotics in mouse macrophages in response to viable Gram-positive and Gram-negative bacteria

We have investigated effects of beta-lactam antibiotics on TNF-alpha, and NOS production from mouse peritoneal macrophages following co-culture with Escherichia coli or Staphylococcus aureus bacteria. Ceftazidime and aztreonam enhanced TNF-alpha secretion from macrophages stimulated with E coli; however, imipenem. does not alter either the kinetics or magnitude of TNF-a in E coli-treated macrophages. Similar treatments with S. aureus co-cultured with macrophages markedly altered profiles of TNF-alpha response characterized by apparent early TNF-alpha peak relative to untreated S. aureus. All antibiotics increased E coli-induced NOS expression as assessed by both mRNA and protein. These same antibiotics significantly reduced S. aureus-induced NOS levels of RNA. Both ceftazidime and aztreonam. enhanced LPS release from E coli in comparison to low-level LPS release from imipenem-treated bacteria, consistent with observed differences in TNF-alpha release. Incubation of all three antibiotics with S, aureus similarly increased levels of the cell wall constituent protein A detected in supernatants at early time points indicating microbial lysis. In parallel, S. aureus culture supernatants from 2-h incubation with antibiotics enhanced TNF-alpha release. These results indicate that different cellular mechanisms contribute to antibiotic-mediated regulation of TNF-a and NOS secretion in mouse macrophages in response to E coli versus S. aureus.