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(Journal of Leukocyte Biology. 2001;69:631-638.)
© 2001 by Society for Leukocyte Biology

Differential effects of 15-deoxy-^12,14-prostaglandin J₂ and a peroxisome proliferator-activated receptor agonist on macrophage activation

Kelly Guyton^*, Robert Bond, Chris Reilly, Gary Gilkeson, Perry Halushka^, and James Cook^¶

Departments of
^* Microbiology and Immunology,
Medicine,
Pharmacology, and
^¶ Physiology and Neuroscience, Medical University of South Carolina, Charleston; and
Department of Pharmacology and Physiology, University of South Carolina School of Medicine, Columbia

Correspondence: James A. Cook, Ph.D., Professor of Physiology/Neuroscience, Medical University of South Carolina, 167 Ashley Ave. Suite 607, Charleston, SC 29425. E-mail: cookja{at}musc.edu

Prostaglandin J₂ metabolite 15-deoxy-^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 (PPAR), but 15-PGJ₂ may exhibit effects independent of PPAR. We hypothesized that 15-PGJ₂ modulates macrophage (M) mediator production by acting on cell signaling proteins upstream of PPAR. The effects of 15-PGJ₂ on bacterial endotoxin LPS-induced rat peritoneal M mediator production were compared with those of a specific PPAR 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-, and thromboxane B₂ (TxB₂). Equimolar concentrations of PGD₂ and CICA significantly inhibited LPS-stimulated TNF- but not NO, and CICA increased TxB₂ production. BRL inhibited LPS-induced NO, but augmented LPS-induced TNF- and TxB₂. 15-PGJ₂ also inhibited degradation of LPS-induced IB 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 M mediator production and cell signaling may occur in part through reactivity of its cyclopentenone ring.

Key Words: BRL 49653 • ERK 1/2 • IB • NO • TNF- • TxB₂

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