Department of Cardiology, Suzhou Kowloon Hospital of Shanghai Jiaotong University School of Medicine, #118 Wansheng Street, Suzhou 215021, Jiangsu, China.
Heart Failure Center, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Chengdu, 610072, China.
Int Immunopharmacol. 2019 Mar;68:218-225. doi: 10.1016/j.intimp.2018.12.066. Epub 2019 Jan 15.
Inducible nitric oxide synthase (iNOS) is a molecule critical for the development of inflammation-associated disorders. Its induction should be tightly controlled in order to maintain cellular homeostasis. Upon lipopolysaccharide (LPS) stimulation, iNOS, in most settings, is induced by the activation of inhibitor of κB-α (IκB-α)-nuclear factor κB (NF-κB) signaling. Farnesyl thiosalicylic acid (FTS), a synthetic small molecule that is considered to detach Ras from the inner cell membrane, has been shown to exhibit numerous anti-inflammatory functions. However, it remains unclear whether and how it affects iNOS induction in macrophages. The present study addressed this issue in cultured macrophages and endotoxemic mice. Results showed that FTS pretreatment significantly prevented LPS-induced increases in iNOS protein and mRNA expression levels in murine cultured macrophages, which were confirmed in organs in vivo from endotoxemic mice, such as the liver and lung. Mechanistic studies revealed that FTS pretreatment did not affect IκB-α degradation and NF-κB activation in LPS-treated macrophages. The nuclear transport of the active NF-κB was also not affected by FTS. But FTS pretreatment reduced the binding of NF-κB to its DNA elements, and reduced NF-κB bindings to iNOS promoter inside LPS-treated macrophages. Finally, our results showed that FST pretreatment increased mouse survival rate compared to LPS alone treatment. Taken together, these results indicate that FTS attenuates iNOS induction in macrophages likely through inhibition of iNOS mRNA transcription, providing further insight into the molecular mechanism of action of FTS in inflammatory disorder therapy.
诱导型一氧化氮合酶（iNOS）是与炎症相关疾病发展相关的关键分子。为了维持细胞内稳态，其诱导应受到严格控制。在脂多糖（LPS）刺激下，iNOS 在大多数情况下，通过抑制κB-α（IκB-α）-核因子κB（NF-κB）信号的激活而被诱导。法呢基硫代水杨酸（FTS）是一种合成的小分子，被认为可以使 Ras 从细胞内膜上脱离，已被证明具有多种抗炎作用。然而，它是否以及如何影响巨噬细胞中 iNOS 的诱导仍不清楚。本研究在培养的巨噬细胞和内毒素血症小鼠中解决了这个问题。结果表明，FTS 预处理可显著防止 LPS 诱导的小鼠培养巨噬细胞中 iNOS 蛋白和 mRNA 表达水平的增加，这在内毒素血症小鼠的体内器官中得到了证实，如肝脏和肺部。机制研究表明，FTS 预处理不影响 LPS 处理的巨噬细胞中 IκB-α 的降解和 NF-κB 的激活。NF-κB 的核转运也不受 FTS 的影响。但是，FTS 预处理减少了 NF-κB 与其 DNA 元件的结合，并且减少了 NF-κB 在 LPS 处理的巨噬细胞内与 iNOS 启动子的结合。最后，我们的结果表明，与 LPS 单独处理相比，FST 预处理可提高小鼠的存活率。综上所述，这些结果表明，FTS 通过抑制 iNOS mRNA 的转录来减轻巨噬细胞中 iNOS 的诱导，为 FTS 在炎症性疾病治疗中的作用机制提供了进一步的认识。
