Interleukin-1beta stimulates platelet-activating factor production in U-937 cells modulating both its biosynthetic and catabolic enzymes

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• 作者：Ioanna C. Vlachogianni^a ; ^b ; Tzortzis Nomikos^b ; ^{tnomikos@hua.gr} ; ; Elizabeth Fragopoulou^b ; George M. Stamatakis^a ; Haralambos C. Karantonis^c ; Smaragdi Antonopoulou^b ; Constantinos A. Demopoulos^a
• 关键词：PAF ; platelet-activating factor ; lyso-PAF AT ; acetyl-CoA ; lyso-PAF acetyltransferase ; PAF-CPT ; DTT-insensitive CDP-choline ; 1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase ; PAF-AH ; PAF-acetylhydrolase ; IL-1¦Â ; interleukin-1¦Â ; MAPK ; mitogen-activated
• 刊名：Cytokine
• 出版年：2013
• 出版时间：August, 2013
• 年：2013
• 卷：63
• 期：2
• 页码：97-104
• 全文大小：968 K

文摘

Interleukin-1beta (IL-1¦Â) is a potent agonist of platelet-activating factor (PAF) synthesis. The monocyte-derived PAF may amplify the inflammatory and thrombotic processes. The IL-1¦Â-induced enzymatic alterations leading to increased PAF synthesis are ill-defined. In the present study the last enzymatic activities of the remodeling (acetyl-CoA:lyso-PAF acetyltransferase) and de novo (DTT-insensitive CDP-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase) biosynthetic routes of PAF and its main catabolic enzyme, PAF acetylhydrolase, along with the intracellular and extracellular PAF levels were determined in homogenates and medium of U-937 after their stimulation with recombinant IL-1¦Â.

IL-1¦Â at 2.5 ng/mL induced an early (0.5-3 h) and a late (12 h) elevation of intracellular PAF levels (2-fold). Only a small portion of intracellular PAF (¡«10 % ) was released to the extracellular medium. IL-1¦Â increased lyso-PAF acetyltrasnferase activity which was peaked at 3 h and kept elevated till 12 h. A rapid 1.5-fold increase of cholinephosphotransferase activity was observed in IL-1¦Â stimulated cells. Finally, a transient stimulation of intracellular PAF-AH was induced by IL-1¦Â at 3 h while incubation of U-937 with the PAF acetylhydrolase inhibitor pefabloc in the presence or absence of IL-1¦Â led to a strong sustained increase of intracellular PAF levels.

In conclusion, both biosynthetic routes of PAF, along with its degradation can be modulated by IL-1¦Â in a time-specific manner. The inhibition of PAF acetylhydrolase strongly augments PAF¡¯s intracellular levels implying its crucial role for the regulation of cellular PAF. The regulation of PAF¡¯s enzymatic machinery under inflammatory conditions is more complicated than we thought to be.