Kagami Shin-ichiro, Kanari Hiroko, Suto Akira, Fujiwara Michio, Ikeda Kei, Hirose Koichi, Watanabe Norihiko, Iwamoto Itsuo, Nakajima Hiroshi
Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan.
Int Arch Allergy Immunol. 2008;146 Suppl 1:61-6. doi: 10.1159/000126063. Epub 2008 May 27.
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key rate-limiting enzyme in the mevalonate pathway. Accumulating data suggest that statins exhibit anti-inflammatory effects on a number of experimental models including experimental autoimmune encephalomyelitis and antigen-induced allergic airway inflammation. However, the mechanism underlying the anti-inflammatory effect of statins is still largely unknown. In this study, we examined the effect of a representative statin, simvastatin, on proinflammatory cytokine production from murine mast cells.
Bone marrow-derived mast cells (BMMCs) were stimulated with lipopolysaccharide (LPS) in the presence or absence of simvastatin, and TNF-alpha and IL-6 production from BMMCs was evaluated at mRNA and protein levels. The effect of simvastatin on the expression of tristetraprolin, an RNA-binding protein that promotes decay of TNF-alpha mRNA, was evaluated.
Incubation of BMMCs with simvastatin resulted in the inhibition of LPS-induced TNF-alpha production at both mRNA and protein levels. Simvastatin also inhibited IL-6 production from LPS-stimulated BMMCs. However, simvastatin did not enhance the expression of tristetraprolin.
Simvastatin inhibits the production of TNF-alpha and IL-6 from activated mast cells in part by inhibiting de novo synthesis of their transcripts and the inhibition may account for the anti-inflammatory effect of simvastatin.
他汀类药物可抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶，这是甲羟戊酸途径中的一种关键限速酶。越来越多的数据表明，他汀类药物在包括实验性自身免疫性脑脊髓炎和抗原诱导的过敏性气道炎症在内的多种实验模型中表现出抗炎作用。然而，他汀类药物抗炎作用的潜在机制仍 largely unknown。在本研究中，我们检测了一种代表性他汀类药物辛伐他汀对小鼠肥大细胞促炎细胞因子产生的影响。
在存在或不存在辛伐他汀的情况下，用脂多糖（LPS）刺激骨髓来源的肥大细胞（BMMCs），并在mRNA和蛋白质水平评估BMMCs中肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的产生。评估了辛伐他汀对促进TNF-α mRNA降解的RNA结合蛋白锌指蛋白36（Tristetraprolin）表达的影响。
用辛伐他汀孵育BMMCs导致在mRNA和蛋白质水平均抑制LPS诱导的TNF-α产生。辛伐他汀还抑制LPS刺激的BMMCs中IL-6的产生。然而，辛伐他汀并未增强锌指蛋白36的表达。
辛伐他汀部分通过抑制其转录本的从头合成来抑制活化肥大细胞中TNF-α和IL-6的产生，这种抑制作用可能解释了辛伐他汀的抗炎作用。
