5-Lipoxygenase contributes to PPAR¦Ã activation in macrophages in response to apoptotic cells
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- 作者：Andreas von Knethen ; Lisa K. Sha ; Laura Kuchler ; Annika K. Heeg ; Dominik Fuhrmann ; Heinrich Heide ; Ilka Wittig ; Thorsten J. Maier ; Dieter Steinhilber ; Bernhard Br¨¹ne
- 关键词：5-LO ; 5-lipoxygenase ; AC ; apoptotic cell(s) ; CV ; control virus ; d/n ; dominant negative ; F5 ; fraction 5 ; FF ; firefly ; FLAP ; 5-LO activating protein ; LC ; living cell(s) ; LR ; lipid raft(s) ; Luc ; luciferase ; M ; marker ; M¦µ ; macrophage(s) ; mß ; CDT ; methyl-
- 刊名：Cellular Signalling
- 出版年：2013
- 出版时间：December, 2013
- 年：2013
- 卷：25
- 期：12
- 页码：2762-2768
- 全文大小：977 K
文摘
Macrophage polarization to an anti-inflammatory phenotype upon contact with apoptotic cells is a contributing hallmark to immune suppression during the late phase of sepsis. Although the peroxisome proliferator-activated receptor ¦Ã (PPAR¦Ã) supports this macrophage phenotype switch, it remains elusive how apoptotic cells activate PPAR¦Ã. Assuming that a molecule causing PPAR¦Ã activation in macrophages originates in the cell membrane of apoptotic cells we analyzed lipid rafts from apoptotic, necrotic, and living human Jurkat T cells which showed the presence of 5-lipoxygenase (5-LO) in lipid rafts of apoptotic cells only. Incubating macrophages with lipid rafts of apoptotic, but not necrotic or living cells, induced PPAR responsive element (PPRE)-driven mRuby reporter gene expression in RAW 264.7 macrophages stably transduced with a 4xPPRE containing vector. Experiments with lipid rafts of apoptotic murine EL4 T cells revealed similar results. To verify the involvement of 5-LO in activating PPAR¦Ã in macrophages, Jurkat T cells were incubated with the 5-LO inhibitor MK-866 prior to induction of apoptosis, which failed to induce mRuby expression. Similar results were obtained with lipid rafts of apoptotic EL4 T cells preexposed to the 5-LO inhibitors zileuton and CJ-13610. Interestingly, Jurkat T cells overexpressing 5-LO failed to activate PPAR¦Ã in macrophages, while their 5-LO overexpressing apoptotic counterparts did. Our results suggest that during apoptosis 5-LO gets associated with lipid rafts and synthesizes ligands that in turn stimulate PPAR¦Ã in macrophages.