Acylation of lysophosphatidylcholine plays a key role in the response of monocytes to lipopolysaccharide.
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.
Schmid
Bernhard
B
School of Biosciences, Cardiff University, UK.
Finnen
Michael J
MJ
Harwood
John L
JL
Jackson
Simon K
SK
D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000215:Acylation; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000737:chemistry / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D015394:Molecular Structure; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008244:Lysophosphatidylcholines; D009943:Organophosphorus Compounds; C093303:SK&F 98625; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008243:1-Acylglycerophosphocholine O-Acyltransferase