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

Abstract

We have investigated effects of β-lactam antibiotics on TNF-α, and iNOS production from mouse peritoneal macrophages following co-culture with Escherichia coli or Staphylococcus aureus bacteria. Ceftazidime and aztreonam enhanced TNF-α secretion from macrophages stimulated with E. coli; however, imipenem does not alter either the kinetics or magnitude of TNF-α in E. coli -treated macrophages. Similar treatments with S. aureus co-cultured with macrophages markedly altered profiles of TNF-α response characterized by apparent early TNF-α peak relative to untreated S. aureus. All antibiotics increased E. coli-induced iNOS expression as assessed by both mRNA and protein. These same antibiotics significantly reduced S. aureus-induced iNOS 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-α 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-α release. These results indicate that different cellular mechanisms contribute to antibiotic-mediated regulation of TNF-α and iNOS secretion in mouse macrophages in response to E. coli versus S. aureus.