title: PGE2/EP4 signaling in peripheral immune cells promotes development of experimental autoimmune encephalomyelitis.
abstract: Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory autoimmune disease model of multiple sclerosis (MS). The inflammatory process is initiated by activation and proliferation of T cells and monocytes and by their subsequent migration into the central nervous system (CNS), where they induce demyelination and neurodegeneration. Prostaglandin E2 (PGE2) - synthesized by cyclooxygenase 2 (COX-2) - has both pro- and anti-inflammatory potential, which is translated via four different EP receptors. We hypothesized that PGE2 synthesized in the preclinical phase by peripheral immune cells exerts pro-inflammatory properties in the EAE model. To investigate this, we used a bone marrow transplantation model, which enables PGE2 synthesis or EP receptor expression to be blocked specifically in peripheral murine immune cells. Our results reveal that deletion of COX-2 or its EP4 receptor in bone marrow-derived cells leads to a significant delay in the onset of EAE. This effect is due to an impaired preclinical inflammatory process indicated by a reduced level of the T cell activating interleukin-6 (IL-6), reduced numbers of T cells and of the T cell secreted interleukin-17 (IL-17) in the blood of mice lacking COX-2 or EP4 in peripheral immune cells. Moreover, mice lacking COX-2 or EP4 in bone marrow-derived cells show a reduced expression of matrix metalloproteinase 9 (MMP9), which results in decreased infiltration of monocytes and T cells into the CNS. In conclusion, our data demonstrate that PGE2 synthesized by monocytes in the early preclinical phase promotes the development of EAE in an EP4 receptor dependent manner.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. Electronic address: susanne.schiffmann@med.uni-frankfurt.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schiffmann
authors.affiliation: Institut für Biochemie, Fachbereich Medizin, Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Männich
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Eberle
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Birod
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiros
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Schreiber
authors.affiliation: Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany.
authors.forename: Hana
authors.initials: H
authors.lastname: Kunkel
authors.affiliation: Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Grez
authors.affiliation: Institut für Biochemie, Fachbereich Medizin, Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weichand
authors.affiliation: Institut für Biochemie, Fachbereich Medizin, Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, Schleusenweg 2-16, 60528 Frankfurt/Main, Germany.
authors.forename: Waltraud
authors.initials: W
authors.lastname: Pfeilschifter
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Nüsing
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology* / Q000473:pathology; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone
keywords: Cyclooxygenase-2; Interleukin-17; Interleukin-6; Matrix metalloproteinase 9; Multiple sclerosis; Prostaglandin E2