Article Text

PDF
FRI0017 Role of prostaglandins in the inflammatory reflex: Impaired vagus-mediated immunosuppression in mice deficient in microsomal prostaglandin E synthase-1 (MPGES-1)
  1. E. Le Maitre,
  2. P. Revathikumar,
  3. H. Idborg,
  4. M. Korotkova,
  5. P.-J. Jakobsson,
  6. J. Lampa
  1. Dep of Medicine, Rheumatology unit, CMM, Karolinska Institute, Stockholm, Sweden

Abstract

Background The cholinergic anti-inflammatory pathway (i.e. inflammatory reflex) comprises an important neuro-immune link whereby inflammation such as arthritis can be tightly controlled by the autonomic nervous system and the vagus nerve (VN). Prostaglandins are known to mediate central effects in neurotransmission, by modulating glial interaction with neurons.

Objectives We have investigated the role of prostaglandins, including the major prostaglandin E2 producing enzyme mPGES-1, in the cholinergic anti-inflammatory pathway.

Methods Knock-out mice for the mPGES-1 enzyme (-/-) have been used for the study, with comparison to wild-type (+/+) animals. After VN isolation, we injected intraperitoneally lipopolysaccharides (LPS, 2 mg/kg). We then electrically stimulated the VN for 5 minutes. After a recovery of 6 hours, mice were sacrificed and blood was collected. TNFa, IL-1b and other pro-inflammatory cytokines were measured using the Meso Scale instrument. In addition, we evaluated the effect of PGE2 on the release of cytokines in vitro, using peripheral blood mononuclear cells (PBMC) stimulated by LPS for 20 hours. Supernatants were analyzed for TNFa concentration with ELISA.

Results After Vagus Nerve stimulation (VNS) and analysis of the serum, wild-type animals showed a decrease of the release of TNFa (62.6±8.5 with VNS vs. 90.3±9.1 pg/ml without VNS; p<0.05), IL-1b (70.5±11,0 vs. 114.0±15.6 pg/ml; p<0.05), IL-12p70 (16,521.9±2,014.6 vs. 25,762.4±2,494.6 pg/ml; p<0.01) and IFNg (173.5±38.7 vs. 454.6±111.9; p<0.05). All other cytokines measured with the Meso Scale kit did not differ from the respective controls (i.e. IL-2, IL-4, IL-5, IL-10, KC/GRO). Interestingly, VNS had no effect on any of the cytokines measured on serum from the mPGES-1 knock-out mice. On in vitro studies, incubation with PGE2 (1 μM) was shown to inhibit the release of TNFa by PBMC after LPS stimulation from 375.1±73.7 to 45.5±22.1 pg/ml (p<0.01).

Conclusions Our data indicate that mice deficient in mPGES-1 do not respond to vagus-mediated immunosuppression. Moreover, we show immunosuppressant effects of PGE2 on TNF release. These results implicate an involvement of PGE2 as an important mediator in the cholinergic anti-inflammatory pathway, and provide support for further investigations regarding the interaction between cholinergic and prostaglandin systems.

Disclosure of Interest None Declared

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.