15-deoxy-Delta12,14-prostaglandin J2 inhibits glucocorticoid binding and signaling in macrophages through a peroxisome proliferator-activated receptor gamma-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.
Cheron
Adeline
A
Institut National de la Sante et de la Recherche Medicale, Unite 489, Service d'Explorations Fonctionnelles Multidisciplinaires, AP-HP Hopital Tenon, 4 rue de la Chine, 75020 Paris, France.
Peltier
Julie
J
Perez
Joëlle
J
Bellocq
Agnès
A
Fouqueray
Bruno
B
Baud
Laurent
L
D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics; D003517:Cyclopentanes / Q000494:pharmacology; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000378:metabolism; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D011869:Radioligand Assay; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D020298:U937 Cells
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D018932:Chemokine CCL2; D003517:Cyclopentanes; D005938:Glucocorticoids; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D003907:Dexamethasone; C013905:cyclopentenone; D015230:Prostaglandin D2