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Article |
1 attenuates cytosol to membrane translocation of PKC
to desensitize monocytes/macrophages
Correspondence to Andreas von Knethen: v_knethen{at}zbc.kgu.de
Recently, we provided evidence that PKC
depletion in monocytes/macrophages contributes to cellular desensitization during sepsis. We demonstrate that peroxisome proliferator–activated receptor 
(PPAR) agonists dose dependently block PKC depletion in response to the diacylglycerol homologue PMA in RAW 264.7 and human monocyte–derived macrophages. In these cells, we observed PPAR-dependent inhibition of nuclear factor-
B (NF-B) activation and TNF- expression in response to PMA. Elucidating the underlying mechanism, we found PPAR1 expression not only in the nucleus but also in the cytoplasm. Activation of PPAR1 wild type, but not an agonist-binding mutant of PPAR1, attenuated PMA-mediated PKC cytosol to membrane translocation. Coimmunoprecipitation assays pointed to a protein–protein interaction of PKC and PPAR1, which was further substantiated using a mammalian two-hybrid system. Applying PPAR1 mutation and deletion constructs, we identified the hinge helix 1 domain of PPAR1 that is responsible for PKC binding. Therefore, we conclude that PPAR1-dependent inhibition of PKC translocation implies a new model of macrophage desensitization. 
12,14-prostaglandin J2; AF, activating function; CHX, cycloheximide; DAG, diacylglycerol; DBD, DNA-binding domain; DGK, DAG kinase ; EMSA, electrophoretic mobility shift assay; HEK, human embryonic kidney; IL, interleukin; LBD, ligand-binding domain; MCS, multicloning site; NF-B, nuclear factor-B; PPAR, peroxisome proliferator–activated receptor ; ROS, reactive oxygen species. 
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