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5-Lipoxygenase contributes to PPARγ activation in macrophages in response to apoptotic cells

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  • Andreas von Knethen, Institute of Biochemistry I-Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Electronic address: vonknethen@biochem.uni-frankfurt.de., Ukendt
  • Lisa K Sha, Ukendt
  • Laura Kuchler, Ukendt
  • Annika K Heeg, Ukendt
  • Dominik Fuhrmann, Ukendt
  • Heinrich Heide, Ukendt
  • Ilka Wittig, Ukendt
  • Thorsten Maier, Danmark
  • Dieter Steinhilber
  • ,
  • Bernhard Brüne, Ukendt

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 γ (PPARγ) supports this macrophage phenotype switch, it remains elusive how apoptotic cells activate PPARγ. Assuming that a molecule causing PPARγ 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 PPARγ 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 PPARγ 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 PPARγ in macrophages.

OriginalsprogEngelsk
TidsskriftCellular Signalling
Vol/bind25
Nummer12
Sider (fra-til)2762-8
Antal sider7
ISSN0898-6568
DOI
StatusUdgivet - dec. 2013

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