Activation of Nicotinic Receptors Inhibits TNF-α-Induced Production of Pro-inflammatory Mediators Through the JAK2/STAT3 Signaling Pathway in Fibroblast-Like Synoviocytes

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• 作者：Tong Li ; Shiyao Wu ; Huali Zhang ; Yanping Wang ; Hui Luo ; Xiaoxia Zuo…
• 关键词：nicotinic receptor ; inflammation ; rheumatoid arthritis ; STAT ; jak
• 刊名：Inflammation
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：38
• 期：4
• 页码：1424-1433
• 全文大小：728 KB
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• 作者单位：Tong Li (1)
  Shiyao Wu (1)
  Huali Zhang (2)
  Yanping Wang (1)
  Hui Luo (1)
  Xiaoxia Zuo (1)
  Xianzhong Xiao (2)
  
  1. Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China
  2. Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410008, People’s Republic of China
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Rheumatology
  Internal Medicine
  Pharmacology and Toxicology
  Pathology
  
• 出版者：Springer Netherlands
• ISSN：1573-2576

文摘

It was recently demonstrated that stimulation of the nicotine receptor attenuates collagen-induced arthritis and inhibits cytokine release in mice. We elucidated the possible intracellular signaling mechanism of the cholinergic anti-inflammatory pathway in fibroblast-like synoviocytes (FLSs). Levels of interleukin (IL)-6, IL-10, and monocyte chemoattractant protein (MCP)-1 in culture supernatants of tumor necrosis factor (TNF)-α-stimulated FLSs were measured using an enzyme-linked immunosorbent assay (ELISA). FLSs were transfected with a small interfering RNA oligonucleotide (STAT3 siRNA or control siRNA). AG490, a specific inhibitor of JAK2, was added 16?h before nicotine, and blocker of nAChR was added 30?min before nicotine. Activation of signal transducers and activators of transcription (STAT) such as STAT1 and STAT3 were detected using Western blotting. Nicotine downregulated production of IL-6 and MCP-1 in RA-FLSs induced by TNFα in a concentration-dependent manner, and IL-10 levels were not significantly different after nicotine pretreatment. Nicotine-induced activation of STAT3 (but not STAT1) and deactivation of STAT3 decreased the anti-inflammatory effect of nicotine. AG490 inhibited the phosphorylation of STAT1 and STAT3 and decreased the TNF-α-induced production of pro-inflammatory mediators in RA-FLSs. A α7nAChR antagonist abrogated the anti-inflammatory effects of nicotine and suppressed STAT3 activity. In conclusion, nicotine has an anti-inflammatory effect on RA by downregulating production of IL-6 and MCP-1 in FLSs, and this is mediated through activation of the JAK2–STAT3 signal pathway.