title: Impaired vagus-mediated immunosuppression in microsomal prostaglandin E synthase-1 deficient mice.
abstract: The cholinergic anti-inflammatory pathway controls innate immune responses and inflammation. The prostaglandin (PG) system is involved in several neuro-processes and associated with inflammatory activation of cells in vagal nuclei. Here we aimed to investigate the potential role of PG in cholinergic neuro-regulation. The effect of vagus nerve stimulation (VNS) has been evaluated in microsomal prostaglandin E synthase-1 (mPGES-1) knockout (-/-) and wild-type (+/+) mice regarding cytokine and PG levels after lipopolysaccharides (LPS) challenge. As expected, VNS decreased the release of pro-inflammatory cytokines both in serum and spleen extracts of mPGES-1 (+/+)animals. However, the immune suppressive effect of VNS was completely abolished in mPGES-1 (-/-) mice. The PG content was not affected by VNS in the spleen of mPGES-1 (+/+) and mPGES-1 (-/-) mice but interestingly, acetylcholine (ACh) release in spleen induced by VNS confirmed an intact cholinergic pathway in mPGES-1 (+/+) whereas no VNS-induced ACh release was found in mPGES-1 (-/-) animals. Our data show that mPGES-1 and consequently PGE2 are crucial in the cholinergic anti-inflammatory pathway. Moreover, the mechanisms involved do not affect PG content in the spleen, but lack of mPGES-1 was found to strongly affect cholinergic mechanisms in the inflamed spleen. These findings illustrate previously unrecognized associations between the cholinergic and prostaglandin systems, and may be of importance for further development of therapeutic strategies directed at modulation of the inflammatory reflex, and immunosuppression in chronic inflammatory diseases.
authors.affiliation: Department of Medicine, Unit of Rheumatology, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Electronic address: erwan.lemaitre@ki.se.
authors.forename: Erwan
authors.initials: E
authors.lastname: Le Maître
authors.affiliation: Department of Medicine, Unit of Rheumatology, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Priya
authors.initials: P
authors.lastname: Revathikumar
authors.affiliation: Department of Medicine, Unit of Rheumatology, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Idborg
authors.affiliation: Department of Medicine, Unit of Rheumatology, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Joan
authors.initials: J
authors.lastname: Raouf
authors.affiliation: Department of Medicine, Unit of Rheumatology, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Marina
authors.initials: M
authors.lastname: Korotkova
authors.affiliation: Department of Medicine, Unit of Rheumatology, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.affiliation: Department of Medicine, Unit of Rheumatology, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Jon
authors.initials: J
authors.lastname: Lampa
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D059329:Cholinergic Neurons / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D020297:Mice, Congenic; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D015213:Neuroimmunomodulation; D000071876:Prostaglandin-E Synthases; D013154:Spleen / Q000201:enzymology* / Q000276:immunology / Q000294:innervation / Q000378:metabolism; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000517:prevention & control; D014630:Vagus Nerve / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D020421:Vagus Nerve Diseases / Q000209:etiology / Q000517:prevention & control; D055536:Vagus Nerve Stimulation
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone; D000109:Acetylcholine
keywords: Cholinergic anti-inflammatory pathway; PGE(2); Prostaglandins; Vagus nerve stimulation; mPGES-1 knockout mice