Acylation of lysophosphatidylcholine plays a key role in the response of monocytes to lipopolysaccharide

Eur J Biochem. 2003 Jul;270(13):2782-8. doi: 10.1046/j.1432-1033.2003.03649.x.

Abstract

Mononuclear phagocytes play a pivotal role in the progression of septic shock by producing tumor necrosis factor-alpha (TNF-alpha) and other inflammatory mediators in response to lipopolysaccharide (LPS) from Gram-negative bacteria. Our previous studies have shown monocyte and macrophage activation correlate with changes in membrane phospholipid composition, mediated by acyltransferases. Interferon-gamma (IFN-gamma), which activates and primes these cells for enhanced inflammatory responses to LPS, was found to selectively activate lysophosphatidylcholine acyltransferase (LPCAT) (P < 0.05) but not lysophosphatidic acid acyltransferase (LPAAT) activity. When used to prime the human monocytic cell line MonoMac 6, the production of TNF-alpha and interleukin-6 (IL-6) was approximately five times greater in cells primed with IFN-gamma than unprimed cells. Two LPCAT inhibitors SK&F 98625 (diethyl 7-(3,4,5-triphenyl-2-oxo2,3-dihydro-imidazole-1-yl)heptane phosphonate) and YM 50201 (3-hydroxyethyl 5,3'-thiophenyl pyridine) strongly inhibited (up to 90%) TNF-alpha and IL-6 production in response to LPS in both unprimed MonoMac-6 cells and in cells primed with IFN-gamma. In similar experiments, these inhibitors also substantially decreased the response of both primed and unprimed peripheral blood mononuclear cells to LPS. Sequence-based amplification methods showed that SK&F 98625 inhibited TNF-alpha production by decreasing TNF-alpha mRNA levels in MonoMac-6 cells. Taken together, the data from these studies suggest that LPCAT is a key enzyme in both the pathways of activation (priming) and the inflammatory response to LPS in monocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Acylglycerophosphocholine O-Acyltransferase / antagonists & inhibitors
  • 1-Acylglycerophosphocholine O-Acyltransferase / metabolism*
  • Acylation
  • Cell Line
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Humans
  • Imidazoles / metabolism
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / pharmacology*
  • Lysophosphatidylcholines / chemistry
  • Lysophosphatidylcholines / metabolism*
  • Microsomes / metabolism
  • Molecular Structure
  • Monocytes / cytology
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Organophosphorus Compounds / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Enzyme Inhibitors
  • Imidazoles
  • Interleukin-6
  • Lipopolysaccharides
  • Lysophosphatidylcholines
  • Organophosphorus Compounds
  • SK&F 98625
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • 1-Acylglycerophosphocholine O-Acyltransferase