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Published on: March 24, 2015
Autoregulation of hepatic macrophage activation in sepsis
M A West1, R Manthei, M P Bubrick
1Hennepin County Medical Center, Division of Surgical Infectious Disease, Minneapolis, Minnesota 55415.
Abstract:
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.
Insights
Sepsis alters macrophage regulation. Mediators like tumor necrosis factor (TNF) and prostaglandin E2 (PGE2) from activated macrophages can "autoregulate" their own activation state, impacting sepsis progression.
Area of Science:
- Immunology
- Cell Biology
- Pathophysiology
Background:
- Macrophages play a critical role in sepsis by releasing mediators like TNF and PGE2.
- Dysregulated macrophage activation is implicated in the complex pathophysiology of sepsis.
Purpose of the Study:
- To investigate alterations in macrophage regulation during sepsis.
- To examine the "autoregulatory" role of mediators released by lipopolysaccharide (LPS)-stimulated macrophages on their own activation state.
- To understand how hepatic macrophages (hMøs) regulate hepatocyte protein synthesis in the context of sepsis.
Main Methods:
- In vitro pretreatment of hepatic macrophages (hMøs) with TNF alpha, PGE2, subactivating LPS concentrations, or LPS plus indomethacin.
- Co-culture experiments to assess LPS dose-response relationships for inhibition of hepatocyte protein synthesis.
- Evaluation of changes in hMø responsiveness following pre-exposure to various stimuli.
Main Results:
- Pre-exposure to LPS caused a dose-dependent decrease in subsequent LPS-triggered hMø activation.
- Pretreatment with LPS and indomethacin partially restored hMø responsiveness.
- Pre-exposure to PGE2 significantly reduced LPS responsiveness, suggesting a PGE2-mediated autoregulatory effect.
- TNF alpha pretreatment lowered the LPS concentration required for maximal hMø activation.
Conclusions:
- Macrophage activation state is modulated by both macrophage-derived mediators and prior LPS exposure.
- These findings support an "autoregulatory" mechanism involving mediators from LPS-stimulated macrophages in the context of sepsis.
- Understanding these autoregulatory pathways is crucial for developing targeted sepsis therapies.
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