tailieunhanh - Báo cáo khoa học: Acylation of lysophosphatidylcholine plays a key role in the response of monocytes to lipopolysaccharide

Mononuclear phagocytes play a pivotal role in the pro-gression of septic shock by producing tumor necrosis factor-a(TNF-a) andother inflammatorymediators in response to lipopolysaccharide (LPS) previous studies have shown monocyte and macrophage activationcorrelatewithchanges inmembranephospholipid composition, mediated by acyltransferases. Interferon-c (IFN-c), which activates and primes these cells for enhanced inflammatory responses to LPS, was found to selectively activate lysophosphatidylcholine acyltransferase (LPCAT) (P. | Eur. J. Biochem. 270 2782-2788 2003 FEBS 2003 doi Acylation of lysophosphatidylcholine plays a key role in the response of monocytes to lipopolysaccharide Bernhard Schmid1 2 Michael J. Finnen3 John L. Harwood1 and Simon K. Jackson2 1 School of Biosciences Cardiff University UK 2University of Wales College of Medicine Cardiff UK and 3 Yamanouchi Research Institute Oxford UK Mononuclear phagocytes play a pivotal role in the progression of septic shock by producing tumor necrosis factor-a TNF-a 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-y IFN-y which activates and primes these cells for enhanced inflammatory responses to LPS was found to selectively activate lysophosphatidylcholine acyltransferase LPCAT P but not lysophosphatidic acid acyltransferase LPAAT activity. When used to prime the human monocytic cell line MonoMac 6 the production of TNF-a and interleukin-6 IL-6 was approximately five times greater in cells primed with IFN-y 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-a and IL-6 production in response to LPS in both unprimed MonoMac-6 cells and in cells primed with IFN-y. 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-a production by decreasing TNF-a 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. .