15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Glucocorticoid Binding and Signaling in Macrophages through a Peroxisome Proliferator-Activated Receptor γ-Independent Process

15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) is involved in the control of inflammatory reaction. We tested the hypothesis that 15d-PGJ(2) 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-PGJ(2), and binding experiments were performed with [(3)H]dexamethasone as a glucocorticoid receptor (GR) ligand. 15d-PGJ(2) caused a transient and concentration-dependent decrease in [(3)H]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 gamma (PPARgamma), because the response to 15d-PGJ(2) was neither mimicked by the PPARgamma agonist ciglitazone nor prevented by the PPARgamma antagonist bisphenol A diglycidyl ether. 15d-PGJ(2) 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-PGJ(2), and modification of GR cysteine residues with methyl methanethiosulfonate suppressed the response to 15d-PGJ(2). Finally, 15d-PGJ(2)-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-PGJ(2) limits glucocorticoid binding and signaling in monocytes/macrophages through a PPARgamma-independent and cyclopentenone-dependent mechanism. It provides a way in which 15d-PGJ(2) would exert proinflammatory activities in addition to its known anti-inflammatory activities.