15-Deoxy-Delta12,1412,14-prostaglandin J2 inhibits the beta2 integrin-dependent oxidative burst: involvement of a mechanism distinct from peroxisome proliferator-activated receptor gamma ligation.
15-Deoxy-Delta12,14-PGJ2 (dPGJ2) is a bioactive metabolite of the J2 series that has been identified as a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma) and has received attention for its potential antiinflammatory effects. Because neutrophils express cell-surface receptors for PGs, the effect of dPGJ2 was tested on an inflammatory response that should not require PPARgamma, the oxidative burst made by adherent human neutrophils. dPGJ2 inhibited adhesion-dependent H2O2 production with an IC50 of 1. 5 microM when neutrophils were stimulated with TNF, N-formylnorleucylleucylphenylalanine, or LPS. Inhibition by dPGJ2 occurred during the lag phase, before generation of peroxide, suggesting blockade of an early signaling step. Indeed, dPGJ2 blocked adhesion of neutrophils to fibrinogen in response to TNF or LPS with an IC50 of 3-5 micro+dPGJ2 was more potent at inhibiting the adhesion-dependent oxidative burst than several other PGs tested. Further, dPGJ2 did not appear to act through either the DP receptor or receptors for PGE2. PG receptors modulate cAMP levels, and the inhibition of adhesion and oxidative burst by dPGJ2 was enhanced in the presence of 3-isobutyl-1-methylxanthine, a cAMP phosphodiesterase inhibitor. A potent PPARgamma agonist (AD-5075) did not inhibit peroxide production or adhesion, nor did it change the IC50 for dPGJ2 inhibition. These studies suggest that dPGJ2 may interact with an unknown receptor on neutrophils, distinct from PPARgamma, to modulate the production of reactive oxygen intermediates.
Vaidya
S
S
Merck Research Laboratories, Rahway, NJ 07065, USA.
Somers
E P
EP
Wright
S D
SD
Detmers
P A
PA
Bansal
V S
VS
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D018821:CD18 Antigens / Q000378:metabolism*; D002448:Cell Adhesion; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D009504:Neutrophils / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000037:antagonists & inhibitors
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D018821:CD18 Antigens; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C089947:AD 5075; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor