Mechanism of inhibitory effect of atorvastatin on resistin expression induced by tumor necrosis factor-alpha in macrophages.
Atorvastatin has been shown to reduce resistin expression in macrophages after pro-inflammatory stimulation. However, the mechanism of reducing resistin expression by atorvastatin is not known. Therefore, we sought to investigate the molecular mechanisms of atorvastatin for reducing resistin expression after proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha) stimulation in cultured macrophages. Cultured macrophages were obtained from human peripheral blood mononuclear cells. TNF-alpha stimulation increased resistin protein and mRNA expression and atorvastatin inhibited the induction of resistin by TNF-alpha. Addition of mevalonate induced resistin protein expression similar to TNF-alpha stimulation. However, atorvastatin did not have effect on resistin protein expression induced by mevalonate. SP600125 and JNK small interfering RNA (siRNA) completely attenuated the resistin protein expression induced by TNF-alpha and mevalonate. TNF-alpha induced phosphorylation of Rac, while atorvastatin and Rac-1 inhibitor inhibited the phosphorylation of Rac induced by TNF-alpha. The gel shift and promoter activity assay showed that TNF-alpha increased AP-1-binding activity and resistin promoter activity, while SP600125 and atorvastatin inhibited the AP-1-binding activity and resistin promoter activity induced by TNF-alpha. Recombinant resistin and TNF-alpha significantly reduced glucose uptake in cultured macrophages, while atorvastatin reversed the reduced glucose uptake by TNF-alpha. In conclusion, JNK and Rac pathway mediates the inhibitory effect of atorvastatin on resistin expression induced by TNF-alpha.
Shyu
Kou-Gi
KG
Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. shyukg@ms12.hinet.net
Chua
Su-Kiat
SK
Wang
Bao-Wai
BW
Kuan
Peiliang
P
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D052243:Resistin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D052243:Resistin; D014409:Tumor Necrosis Factor-alpha; D000069059:Atorvastatin; D005947:Glucose