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)alpha 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-2 promoter 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)-kappaB pathway was correlated with the increased production of inflammatory cytokines including tumor necrosis factor-alpha, intercellular adhesion molecule-1, and monocyte chemotactic protein-1. This was eliminated by administration of APN, whereas blockage of PPARalpha 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 PPARalpha-dependent mechanism, and COX-2 exerted an anti-inflammatory effect of APN in hepatocytes subjected to iron challenge.
Lee
Fei-Peng
FP
Department of Otolaryngology, Taipei Medical University-Shuang-Ho Hospital, Taipei, Taiwan.
Jen
Chih-Yu
CY
Chang
Chih-Cheng
CC
Chou
Ying
Y
Lin
Heng
H
Chou
Chih-Ming
CM
Juan
Shu-Hui
SH
D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation; D004790:Enzyme Induction; D011464:Epoprostenol / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000633:toxicity*; D051379:Mice; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D052242:Adiponectin; D047493:PPAR alpha; D034741:RNA, Small Interfering; D011464:Epoprostenol; D007501:Iron; D051546:Cyclooxygenase 2; D015232:Dinoprostone