Mechanisms of adiponectin-mediated COX-2 induction and protection against iron injury in mouse hepatocytes

Adiponectin (APN)-mediated cyclooxygenase (COX)-2 induction is known to have various protective effects on cardiovascular diseases. However, the molecular mechanisms of APN-mediated COX-2 induction and its protection against iron-mediated injury in hepatocytes are still unclear. Herein, we show that AMP-mediated peroxisome proliferator-activated receptor (PPAR)α activation was attributable to COX-2 induction by APN, which was further confirmed by identifying novel functional PPAR responsive elements (PPREs) in the mouse COX-2promoter region. Prostaglandin (PG)I2 and PGE2, metabolites of COX-2, time-dependently increased in hepatocytes treated with APN. Interestingly, beraprost and misoprostol, respective agonists for PGI2 and PGE2, mimicked the protective effects of APN in iron-mediated inflammation in hepatocytes. The iron dextran-activated nuclear factor (NF)-κB pathway was correlated with the increased production of inflammatory cytokines including tumor necrosis factor-α, intercellular adhesion molecule-1, and monocyte chemotactic protein-1. This was eliminated by administration of APN, whereas blockage of PPARα activation, an upstream regulator of COX-2 induction by APN, and COX-2 activation reversed the anti-inflammatory effect of APN, suggesting the crucial role of COX-2 in this event. Herein, we demonstrate that APN-mediated COX-2 induction through a PPARα-dependent mechanism, and COX-2 exerted an anti-inflammatory effect of APN in hepatocytes subjected to iron challenge.