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15-Deoxy-^12,14-Prostaglandin J₂ Inhibits Glucocorticoid Binding and Signaling in Macrophages through a Peroxisome Proliferator-Activated Receptor -Independent Process¹

Institut National de la Santé et de la Recherche Médicale, Unité 489, Service d’Explorations Fonctionnelles Multidisciplinaires, AP-HP Hôpital Tenon, Paris, France

15-Deoxy-^12,14-PGJ₂ (15d-PGJ₂) is involved in the control of inflammatory reaction. We tested the hypothesis that 15d-PGJ₂ would exert this control in part by modulating the sensitivity of inflammatory cells to glucocorticoids. Human U937cells and mouse RAW 264.7 cells were exposed to 15d-PGJ₂, and binding experiments were performed with [³H]dexamethasone as a glucocorticoid receptor (GR) ligand. 15d-PGJ₂ caused a transient and concentration-dependent decrease in [³H]dexamethasone-specific binding to either cells through a decrease in the number of GR per cell without significant modification of the K_d value. These changes were related to functional alteration of the GR rather than to a decrease in GR protein. They did not require the engagement of peroxisome proliferator-activated receptor (PPAR), because the response to 15d-PGJ₂ was neither mimicked by the PPAR agonist ciglitazone nor prevented by the PPAR antagonist bisphenol A diglycidyl ether. 15d-PGJ₂ altered GR possibly through the interaction of its cyclopentenone ring with GR cysteine residues because the cyclopentenone ring per se could mimic the effect of 15d-PGJ₂, and modification of GR cysteine residues with methyl methanethiosulfonate suppressed the response to 15d-PGJ₂. Finally, 15d-PGJ₂-induced decreases in glucocorticoid binding to GR resulted in parallel decreases in the ability of GR to activate the transcription of a glucocorticoid-inducible reporter gene and to reduce the expression of monocyte chemoattractant protein-1. Together these data suggest that 15d-PGJ₂ limits glucocorticoid binding and signaling in monocytes/macrophages through a PPAR-independent and cyclopentenone-dependent mechanism. It provides a way in which 15d-PGJ₂ would exert proinflammatory activities in addition to its known anti-inflammatory activities.

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