The Effects of Vagus Nerve Stimulation on Pro- and Anti-Inflammatory Cytokines in Humans: A Preliminary Report

Abstract

Objective: Vagus nerve stimulation (VNS) is a novel therapy in resistant epilepsy, and is undergoing clinical trials in resistant depression. The mechanism of action of VNS is assumed to be due to modulation of deep brain structures via its afferent connections. As the vagus nerve has potentially important immunological actions that may have relevance to its therapeutic effects, we hypothesised that an additional mechanism may occur via vagally mediated actions on cytokine synthesis. Methods: Patients (n = 10) with resistant depression were studied in the weeks prior to, and 3 months following, implantation of a vagus nerve stimulator. No medication changes were made during the course of the study. High-sensitivity ELISA kits were used to measure plasma IL-1β, IL-6, TNF-α, IL-10 and TGF-β concentrations. C-reactive protein (CRP) was measured using a high sensitivity immunonephelometry assay. Results: There were highly significant increases in the plasma levels of IL-6, TNF-α and TGF-β. Increases seen with IL-10 and IL-1β were not significant. Plasma CRP levels were unchanged. Conclusion: VNS is associated with marked peripheral increases in pro- and anti-inflammatory circulating cytokines. Such changes are unlikely to be non-specific inflammatory reactions, reflected by CRP levels. In view of gathering evidence supporting a role for the immune system in modulating affect, as well as seizure activity, these effects of VNS may be therapeutically relevant.

Vagotomy Induces Deregulation of the Inflammatory Response during the Development of Amoebic Liver Abscess in Hamsters

“…This activation leads to the release of IL-10, IL-12 p40, TNF-α, and IL-8 from human monocytes [39]. The regulating effect of the cholinergic pathway on NFκB has been shown in smokers, acute respiratory distress syndrome, and epilepsy, focusing on the production of pro- and anti-inflammatory cytokines in monocytes during the inflammatory process [40,41,42,43,44]. …”

“…Upon measuring the serum levels of pro- and anti-inflammatory cytokines in these patients, a significant increase was found in IL-6, TNF-α, and TGF-β at the systemic level, without a significant change in IL-1β and IL-10. The result of this type of vagus stimulation was a generally suppressive effect on inflammation resulting from a decrease in circulating proinflammatory cytokines [44]. …”

“…This evidence seems to indicate that a subdiaphragmatic vagotomy produces a different effect than that achieved via VN stimulation [44]. In vitro studies have shown that IL-10 exerts an anti-inflammatory effect by inhibiting the activation of macrophages and the production of IL-1β and TNF-α [61].…”

Neuro-immune interactions during development of pulmonary fibrosis

“…release of neuropeptides) or central reflexes to stimulate ECM production via T-cells, macrophages and fibroblasts. Stimulation of the vagus nerve in patients with depression significantly increased levels of transforming growth factor beta (TGF-β) , a substance which promotes fibrosis [13], while vagotomy eliminated the drug-induced activation of TGF-β in cerebrospinal fluid [14]. ACh can also activate M receptors to promote fibroblast proliferation in the lung [15].…”

Increased vagal tone accounts for the observed immune paralysis in patients with traumatic brain injury

“…38,43,44 In humans, we know of only one study that evaluated inflammatory mediators in patients with a vagus nerve stimulator. 45 In this study, circulating inflammatory mediators were measured before implantation of the stimulator and after 12 weeks following implantation of the stimulator in a small group of patients with severe depression. After stimulator implantation, the proinflammatory mediators TNF␣ and IL-6 were significantly elevated; however, other proinflammatory mediators such as IL-1 and CRP were not.…”