The Effects And Mechanisms Of Vagus Nerve And Acetylcholine Receptor In Experimental Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease, characterized by chronic inflammation of synovial membranes and proliferation of the synovial lining, leading to cartilage damage and ultimately joint destruction. Although the pathogenesis of RA remains unclear, a variety of cytokines have been implicated in the development of the disease. The central nervous system (CNS) is the regulating "hub" of the immune response which can control inflammation on different levels. It has recently been discovered that the efferent vagus nerve signals suppress release of pro-inflammatory cytokines and inhibit inflammation; this novel vagal function was termed the "cholinergic anti-inflammation pathway". Many results show that the cholinergic anti-inflammatory pathway has an important role in acute inflammatory disease, including endotoxemia, trauma, and sepsis. We speculate that the cholinergic anti-inflammatory pathway should also have a protective effect for RA. However, the precise mechanism of protection by cholinergic pathway in RA remains unclear. Therefore, we designed the following experiment.Objectives. The cholinergic anti-inflammatory pathway, a vagus nerve-dependent mechanism, inhibits cytokine releases in models of acute inflammatory disease. We investigated the efficacy and elucidated the possible mechanism of the cholinergic anti-inflammatory pathway on collagen-induced arthritis (CIA) in mice. Methods. Fifty-six male DBA/1 mice were divided into four groups:control mice (sham vagotomy+ phosphate-buffered saline; shamVGX+PBS), model mice (shamVGX+ PBS+CIA), vagotomy mice (VGX+PBS+CIA) and nicotine (Nic) mice (shamVGX+Nic+CIA). We subjected mice to left-side cervical vagotomy four days before induction of arthritis. Mice in the nicotine group were injected with nicotine (250μg/kg per day) four days before arthritis induction. Arthritis score was measured and histopathologic assessment of joint sections carried out. The concentration of tumor necrosis factor (TNF)-a, interleukin (IL)-6 and IL-10 in serum were evaluated by ELISA. Expression of high-mobility group box chromosomal protein 1(HMGB1) was evaluated by immunohistochemical staining of joints. Results. Vagotomy exaggerated, whereas nicotine attenuated, clinical arthritis. Histopathologic findings confirmed that nicotine reduced infiltration of inflammatory cell and bone destruction. Expression of TNF-a and IL-6 decreased in nicotine-pretreated mice compared with model and vagotomy mice; IL-10 levels were not significantly different between the model group and nicotine group. Nicotine reduced the expression and translocation of HMGB1 in the inflamed joints of CIA mice. Conclusions. The cholinergic anti-inflammatory pathway has an anti-inflammatory role in the pathophysiology of CIA mice via inhibiting HMGB1 release and early pro-inflammatory cytokines function.Objectives. 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).Methods. Levels of IL-6, IL-10 and monocyte chemoattractant protein (MCP)-1 in culture supernatants were measured using an ELISA. FLSs were transfected with a small interfering RNA oligonucleotide. Blockers of AG490 added 16 hours before nicotine and nAChR were added 30 min before nicotine. Activation of signal transducers and activators of transcription (STAT) such as STAT1 and STAT3 were detected using western blot. Results. Nicotine downregulated production of IL-6 and MCP-1 in RA-FLSs induced by TNF-a 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 partly abolished the anti-inflammatory effect of nicotine. AG490 inhibited the phosphorylation of STAT1 and STAT3, and decreased the TNF-a-induced production of pro-inflammatory mediators in RA-FLSs. An a7nAChR antagonist abrogated the anti-inflammatory effects of nicotine and suppressed STAT3 activity. Conclusions. Nicotine has an anti-inflammatory effect on RA by downregulatting production of IL-6 and MCP-1 in FLSs, and this is mediated through activation of the Jak2-STAT3 signal pathway.Objectives:SOCS protein play an an important role in the regulation of inflammatory processes. We explore its role in acetylcholine receptor agonists inhibitting cytokine secretion of RA synovial fibroblast-like cells. Methods:Western blot detected the expression of SOCS1 and SOCS3; FLSs transfected with small interfering siRNA oligonucleotides; Levels of IL-6 in culture supernatants were measured using ELISA. Results. Nicotine induced SOCS3 expression in RA FLSs, but nicotine had no effect on the expression of SOCS1; Low expression of SOCS3 abolished the anti-inflammatory effect of nicotine on RA FLSs. Conclusions. The inhibition effect of nicotine on the secretion of inflammatory cytokines is related to the expression of SOCS3 in RA FLSs.