Nuclear receptor Nur77 suppresses inflammatory response dependent on COX-2 in macrophages induced by oxLDL.
Oxidized low-density lipoprotein (oxLDL) cross-talks with macrophages, and both play a crucial role in the initiation and progression of atherosclerosis. Orphan nuclear receptor Nur77 is potently induced in macrophages by diverse stimuli, suggesting that it may be a key regulator of inflammation in vascular cells. The detailed mechanism of Nur77 activation and subsequent function in macrophages induced by oxLDL remains unclearly. In this study, we demonstrated that Nur77 is upregulated in a dose and time-dependent fashion by oxLDL stimulation in murine macrophages, as detected by real-time PCR and Western blotting. OxLDL activated the phosphorylation ERK1/2 and p38 MAPK, inhibition of p38 MAPK but not ERK1/2 attenuated Nur77 expression. Importantly, overexpression of Nur77 suppressed oxLDL-induced proinflammatory cytokines and chemokines secretion including tumor necrosis factor (TNF)alpha and monocyte chemoattractant protein-1(MCP-1). While knockdown Nur77 expression by specific small interfering RNA (siRNA) resulted in the enhancement of the secretion. Furthermore, exposure of macrophages to oxLDL significantly upregulated cyclooxygenase-2(COX-2) expression. However, this could be markedly inhibited by Nur77 overexpression. Also, Nur77 siRNA increased oxLDL-induced COX-2 expression and 6-mercaptopurine (6-MP) attenuated the increase. The results indicated that Nur77 is induced by oxLDL via p38 MAPK signal pathway and subsequently protects against inflammation by the inhibition of proinflammatory COX-2 pathway in activated macrophages. Specifically modifying transcription activity of Nur77 may represent a potential molecular target for the prevention and treatment of atherosclerosis.
Shao
Qin
Q
Department of Cardiology, Medical School of Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Shen
Ling-Hong
LH
Hu
Liu-Hua
LH
Pu
Jun
J
Qi
Mei-Yan
MY
Li
Wen-Qing
WQ
Tian
Fu-Ju
FJ
Jing
Qing
Q
He
Ben
B
D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018925:Chemokines; D016861:Cyclooxygenase Inhibitors; D008077:Lipoproteins, LDL; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C099252:oxidized low density lipoprotein; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases