Farnesyl thiosalicylic acid prevents iNOS induction triggered by lipopolysaccharide via suppression of iNOS mRNA transcription in murine macrophages

• Published in: International immunopharmacology 2019-03, Vol.68, p.218-225
• Main Authors: Wu, Jing-Jing, Yuan, Xiao-Mei, Huang, Chao, An, Guo-Yin, Liao, Zhan-Ling, Liu, Guang-An, Chen, Run-Xiang
• Format: Article
• Language: English
• Subjects: Cell activation; Cell membranes; Deoxyribonucleic acid; DNA; Farnesyl thiosalicylic acid; Gene expression; Homeostasis; In vivo methods and tests; Inflammatory diseases; Inhibitor of κB-α; Lipopolysaccharide; Lipopolysaccharides; Liver; Lungs; Macrophage; Macrophages; Mice; NF-κB protein; Nitric oxide; Nitric-oxide synthase; Nuclear factor κB; Nuclear transport; Organs; Proteins; Rodents; Thiosalicylic acid; Transcription
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2018.12.066

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. •FTS prevents iNOS induction in LPS-treated macrophages.•FTS prevents iNOS protein and mRNA expression in endotoxemic mice.•FTS does not affect LPS-induced IκB-α degradation and NF-κB phosphorylation.•FTS does not affect NF-κB nuclear translocation in LPS-treated macrophages.•FTS reduces NF-κB's binding to the iNOS promoter inside LPS-treated macrophages.