Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School,Charlestown, Massachusetts, USA.
J Pharmacol Exp Ther. 2011 Dec;339(3):832-41. doi: 10.1124/jpet.111.183558. Epub 2011 Aug 26.
Treatment with statins, inhibitors of HMG-CoA reductase, extends the survival of septic mice. However, the molecular mechanisms underlying the cholesterol-lowering, independent beneficial effects of statins in sepsis are poorly understood. The inhibition of protein isoprenylation, namely farnesylation and geranylgeranylation, has been proposed as a mediator of the pleiotropic protective effects of statins, although direct evidence is lacking. Major features of sepsis-induced immune suppression include T-cell dysfunction, which is characterized by apoptosis of splenic T cells, increased CD4(+)Foxp3(+) regulatory T cells (Tregs), and suppression of type 1 helper T-cell response [e.g., interferon-γ (IFN-γ) secretion] in mice. Here, we show that the induction of sepsis by cecal ligation and puncture (CLP) resulted in increases in farnesyltransferase activity and farnesylated proteins in the spleen relative to sham operation. Treatment with farnesyltransferase inhibitor N-[4-[2(R)-amino-3-mercaptopropyl]amino-2-phenylbenzoyl]methionine methyl ester trifluoroacetate salt (FTI-277) (25 mg/kg b.wt. i.p.) at 2 h after CLP blocked the increase in farnesylated proteins and improved survival and bacterial clearance of septic mice. FTI-277 reverted to or mitigated sepsis-induced apoptosis in spleen and thymus, increased splenic CD4(+)Foxp3(+) Tregs, and suppressed IFN-γ secretion and proliferation of splenocytes in response to anti-CD3+CD28 antibodies in mice. Moreover, FTI-277 promoted macrophage phagocytotic activity in septic mice. These results indicate that elevation in protein farnesylation plays a role in derangements in immune function and mortality of septic mice. These findings suggest that prevention of immune dysfunction might contribute to FTI-277-induced improvement in survival of septic mice. These data highlight protein farnesyltransferase as a novel potential molecular target to reduce the mortality of patients with sepsis.
他汀类药物，即 HMG-CoA 还原酶抑制剂，可延长脓毒症小鼠的存活时间。然而，他汀类药物在脓毒症中降低胆固醇和独立发挥有益作用的分子机制尚不清楚。蛋白质异戊烯化的抑制，即法呢基化和香叶基化，已被提议作为他汀类药物多效保护作用的介导物，尽管缺乏直接证据。脓毒症引起的免疫抑制的主要特征包括 T 细胞功能障碍，其特征为脾 T 细胞凋亡、增加的 CD4(+)Foxp3(+)调节性 T 细胞（Tregs）和 1 型辅助 T 细胞反应（例如干扰素-γ（IFN-γ）分泌）的抑制。在这里，我们表明，通过盲肠结扎和穿刺（CLP）诱导脓毒症导致脾中法尼基转移酶活性和法尼基化蛋白增加相对于假手术。在 CLP 后 2 小时用法尼基转移酶抑制剂 N-[4-[2(R)-氨基-3-巯基丙基]氨基-2-苯基苯甲酰基]甲硫氨酸甲酯三氟乙酸盐（FTI-277）（25 mg/kg b.wt. i.p.）治疗可阻止法尼基化蛋白的增加，并改善脓毒症小鼠的存活率和细菌清除率。FTI-277 逆转或减轻脓毒症引起的脾和胸腺细胞凋亡，增加脾 CD4(+)Foxp3(+)Tregs，并抑制 IFN-γ分泌和对 CD3+CD28 抗体的脾细胞增殖。此外，FTI-277 促进脓毒症小鼠中巨噬细胞的吞噬活性。这些结果表明，蛋白质法尼基化的升高在脓毒症小鼠免疫功能障碍和死亡率中起作用。这些发现表明，预防免疫功能障碍可能有助于 FTI-277 改善脓毒症小鼠的存活率。这些数据突出了蛋白质法尼基转移酶作为一种新型潜在的分子靶点，可降低脓毒症患者的死亡率。
