15-Deoxy-Δ 12,14-prostaglandin J 2 inhibits the expression of proinflammatory genes in human blood monocytes via a PPAR-γ-independent mechanism

Abstract

The peroxisome proliferator-activated receptor-γ (PPAR-γ) has been implicated in inhibition of the expression of proinflammatory cytokines and inducible enzymes such as cyclooxygenase-2 (COX-2). Using real-time RT-PCR the present study investigates the impact of two PPAR-γ agonists, 15-deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2) and ciglitazone, on the expression of several proinflammatory genes in lipopolysaccharide (LPS)-stimulated human blood monocytes. Stimulation of cells with LPS resulted in a profound induction of the expression of COX-2, interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Treatment of cells with 15d-PGJ 2 (10 μM) was associated with a nearly complete inhibition of the expression of all genes that remained unaltered in the presence of the PPAR-γ antagonist bisphenol A diglycidyl ether (BADGE; 100 μM). By contrast, treatment of cells with another potent PPAR-γ agonist, ciglitazone (50 μM), and the PPAR-α agonist WY-14,643 (100 μM) did not suppress LPS-induced expression of the investigated genes. Stimulation of monocytes with LPS resulted in an 88% inhibition of PPAR-γ mRNA expression that was fully restored by 15d-PGJ 2 but only to a partial extent by ciglitazone and WY-14,643. Again, BADGE did not alter the effect of 15d-PGJ 2. Collectively, our results show that alterations of gene expression by 15d-PGJ 2 in LPS-stimulated human blood monocytes are mediated by PPAR-γ-independent mechanisms. Moreover, it is concluded that both inhibition of proinflammatory gene expression and restoration of LPS-induced decrease of PPAR-γ expression may contribute to the biological action of 15d-PGJ 2.