Differential effects of 15-deoxy-delta(12,14)-prostaglandin J2 and a peroxisome proliferator-activated receptor gamma agonist on macrophage activation.

Abstract:

:Prostaglandin J2 metabolite 15-deoxy-delta(12,14)-prostaglandin J2 (15-PGJ2) appears to possess anti-inflammatory properties. Unlike other prostaglandins, it has no known plasma membrane receptor. Its effects have been thought to occur through activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma), but 15-PGJ2 may exhibit effects independent of PPARgamma. We hypothesized that 15-PGJ2 modulates macrophage (Mphi) mediator production by acting on cell signaling proteins upstream of PPARgamma. The effects of 15-PGJ2 on bacterial endotoxin LPS-induced rat peritoneal Mphi mediator production were compared with those of a specific PPARgamma agonist, BRL 49653 (BRL), and to the eicosanoids prostaglandin D2 (PGD2) and cicaprost (CICA, a prostacyclin analogue). 15-PGJ2 inhibited LPS-induced production of NO, TNF-alpha, and thromboxane B2 (TxB2). Equimolar concentrations of PGD2 and CICA significantly inhibited LPS-stimulated TNF-alpha but not NO, and CICA increased TxB2 production. BRL inhibited LPS-induced NO, but augmented LPS-induced TNF-alpha and TxB2. 15-PGJ2 also inhibited degradation of LPS-induced IkappaB alpha and phosphoactivation of ERK 1/2, but BRL had no significant effect on either protein. The cyclopentenone ring 2-cyclopenten-1-one also inhibited LPS-induced ERK 1/2 activation; however, neither 15-PGJ2 nor the cyclopentenone inhibited PMA-induced ERK 1/2 activation. Inhibition of LPS-stimulated mediator production by 15-PGJ2 differed from inhibition by PGD2, CICA, and BRL. The ability of 15-PGJ2 to inhibit LPS-induced Mphi mediator production and cell signaling may occur in part through reactivity of its cyclopentenone ring.

journal_name

J Leukoc Biol

authors

Guyton K,Bond R,Reilly C,Gilkeson G,Halushka P,Cook J

subject

Has Abstract

pub_date

2001-04-01 00:00:00

pages

631-8

issue

4

eissn

0741-5400

issn

1938-3673

journal_volume

69

pub_type

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