Statins induce suppressor of cytokine signaling-3 in macrophages.
Our previous study has shown that lipophilic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors of statins can inhibit interferon-gamma-induced inducible nitric oxide synthase gene expression in RAW264.7 macrophages. In this study, we showed that lovastatin and fluvastatin are able to upregulate the mRNA expression of the suppressor of cytokine signaling-3 (SOCS-3) gene. This effect is specific for SOCS-3 and could be blocked by mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, while it was not affected by inhibitors of protein kinase C and A, mitogen-activated protein/extracellular signal-regulated kinase kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, Src, Raf and Rho kinase. SOCS-3 expression results in the inhibition of interferon-gamma-, interleukin-6- and macrophage colony-stimulating factor-elicited signal transducer and activator of transcription phosphorylation, suggesting a novel anti-inflammatory mechanism of statins to down-modulate the functions of interferon-gamma-activated macrophages.
Huang
Kuo-Chin
KC
Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Chen
Ching-Wen
CW
Chen
Jui-Ching
JC
Lin
Wan-Wan
WW
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077340:Fluvastatin; D007211:Indoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008148:Lovastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins; D012717:Sesquiterpenes; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D015850:Interleukin-6; D011106:Polyisoprenyl Phosphates; D047428:Protein Kinase Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D012717:Sesquiterpenes; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000077340:Fluvastatin; C004808:farnesyl pyrophosphate; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D008148:Lovastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid