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12,1412,14-prostaglandin J2 Inhibits the ß2 Integrin-Dependent Oxidative Burst: Involvement of a Mechanism Distinct from Peroxisome Proliferator-Activated Receptor 
Ligation
Merck Research Laboratories, Rahway, NJ 07065
15-Deoxy-
12,14-PGJ2 (dPGJ2)
is a bioactive metabolite of the J2 series that has been
identified as a ligand for peroxisome proliferator-activated receptor
(PPAR) 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 PPAR, the oxidative
burst made by adherent human neutrophils. dPGJ2 inhibited
adhesion-dependent H2O2 production with an
IC50 of 1.5 µM 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 µM.
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 PPAR 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 PPAR, to modulate the production of
reactive oxygen intermediates.
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