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PPARγ1 Attenuates Cytosol to Membrane Translocation of PKCα to Desensitize Monocytes/Macrophages

Andreas von Knethen, Mathias Soller, Nico Tzieply, Andreas Weigert, Axel M. Johann, Carla Jennewein, Roman Köhl and Bernhard Brüne
The Journal of Cell Biology
Vol. 176, No. 5 (Feb. 26, 2007), pp. 681-694
Stable URL: http://www.jstor.org/stable/30049904
Page Count: 14
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PPARγ1 Attenuates Cytosol to Membrane Translocation of PKCα to Desensitize Monocytes/Macrophages
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Abstract

Recently, we provided evidence that PKCα depletion in monocytes/macrophages contributes to cellular desensitization during sepsis. We demonstrate that peroxisome proliferator-activated receptor γ (PPARγ) agonists dose dependently block PKCα depletion in response to the diacylglycerol homologue PMA in RAW 264.7 and human monocyte-derived macrophages. In these cells, we observed PPARγ-dependent inhibition of nuclear factor-κB (NF-κB) activation and TNF-α expression in response to PMA. Elucidating the underlying mechanism, we found PPARγ1 expression not only in the nucleus but also in the cytoplasm. Activation of PPARγ1 wild type, but not an agonist-binding mutant of PPARγ1, attenuated PMA-mediated PKCα cytosol to membrane translocation. Coimmunoprecipitation assays pointed to a protein-protein interaction of PKCα and PPARγ1, which was further substantiated using a mammalian two-hybrid system. Applying PPARγ1 mutation and deletion constructs, we identified the hinge helix 1 domain of PPARγl 1 that is responsible for PKCα binding. Therefore, we conclude that PPARγ1dependent inhibition of PKCα translocation implies a new model of macrophage desensitization.

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