15-Deoxy-DELTA~(12,14)-Prostaglandin J_2 Inhibits Glucocorticoid Binding and Signaling in Macrophages through a Peroxisome Proliferator-Activated Receptor y-Independent Process

摘要

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 [~3H]dexamethasone as a glucocorticoid receptor (GR) ligand.15d-PGJ_2 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 y (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 PPARy-independent and cyclopentenone-dependent mechanism.It provides a way in which 15d-PGJ_2 would exert proinflam-matory activities in addition to its known anti-inflammatory activities.