PGJ2 Inhibition of LPS-induced Inflammatory Mediator Expression from Rat Alveolar Macrophages

Abstract

Studies suggested that 15-deoxy-Δ-^12,14-prostaglandin J₂ (PGJ2) may exert anti-inflammatory effects, including in the lung. Thus, in vitro studies were conducted to (1) investigate whether PGJ2 inhibited the production of inflammatory mediators from lipopolysaccharide (LPS)-exposed primary rat alveolar macrophages (AM), and (2) investigate possible mechanisms underlying PGJ2-mediated inhibition of inflammatory mediator production. These studies determined that PGJ2 inhibited LPS-induced nitric oxide (NO) production in a concentration- and time-dependent manner. PGJ2-mediated inhibition of NO, as well as of tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-2 (MIP-2), was also determined to be dependent on the time of addition of PGJ2 relative to LPS, and suggested the PGJ2 inhibitory mechanism is an early event. PGJ2 was shown not to interfere with binding or internalization of LPS by AM, indicating this was not responsible for PGJ2 inhibitory effects. Another possible mechanism underlying PGJ2-mediated inhibition was via peroxisome proliferator-activated receptor-γ (PPAR-γ). However, biochemical studies suggested that PGJ2-mediated inhibition was not occurring through PPAR-γ dependent mechanism, and molecular studies further established that both LPS and PGJ2 decrease PPAR-γ mRNA expression. A third possible mechanism underlying PGJ2-mediated inhibition was by alteration of nuclear factor (NF)-κB. Molecular studies confirmed that LPS stimulated NF-κB mRNA expression, and PGJ2 reduced this stimulation, which is consistent with PGJ2 effect on LPS-induced production of NO, TNF-α and MIP-2. Thus, data in this study established that PGJ2 inhibited LPS-induced inflammatory mediator production in rat AM, and this inhibition is mediated, at least in part, by reducing the expression of NF-κB mRNA.

The authors express their appreciation to Delores Prugh for her technical assistance and to Dr. Vincent Castranova for his critical discussions during the conduct of the study.

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.