Autoregulation of hepatic macrophage activation in sepsis.
Endotoxin (LPS)-stimulated macrophages release mediators, such as tumor necrosis factor (TNF) and prostaglandin E2 (PGE2), which modulate the function of many different cells. We hypothesize that macrophage regulation is altered in sepsis and that mediators from LPS-stimulated macrophages "autoregulate" their activation state. Alterations in the LPS dose response relationships for inhibition of hepatocyte protein synthesis by hepatic macrophages (hMøs) were examined to investigate factors that regulate hMø activation. In vitro pretreatment was compared using TNF alpha, PGE2, subactivating concentrations of LPS, or LPS plus indomethacin. Pre-exposure to LPS resulted in a dose-dependent loss of subsequent LPS-triggered activation of hMøs in co-culture. Pretreatment with LPS and 1 mumol/L indomethacin partially restored hMø responsiveness. Pre-exposure to PGE2 significantly decreased LPS responsiveness of co-cultured hMøs, suggesting that PGE2 produced by LPS-stimulated hMøs may mediate this effect. Pretreatment of hMøs with TNF alpha, but not IL-1 beta, significantly lowered the LPS concentration required for maximal hMø activation. We conclude that both macrophage mediators and LPS pretreatment alter macrophage activation state. These data suggest an "autoregulatory" role for mediators of LPS-stimulated macrophages in sepsis.
West
M A
MA
Hennepin County Medical Center, Division of Surgical Infectious Disease, Minneapolis, Minnesota 55415.
Manthei
R
R
Bubrick
M P
MP
D001424:Bacterial Infections / Q000276:immunology*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000276:immunology*; D007213:Indomethacin / Q000494:pharmacology; D007728:Kupffer Cells / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation; D015846:Monokines / Q000502:physiology; D014176:Protein Biosynthesis
D008070:Lipopolysaccharides; D015846:Monokines; D015232:Dinoprostone; D007213:Indomethacin