title: Critical role for prokineticin 2 in CNS autoimmunity.
abstract: OBJECTIVE
  To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involved in multiple biological functions including immune modulation, in CNS autoimmune demyelinating disease.
  
  
  METHODS
  We investigated the expression of PK2 in mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), and in patients with relapsing-remitting MS. We evaluated the biological effects of PK2 on expression of EAE and on development of T-cell response against myelin by blocking PK2 in vivo with PK2 receptor antagonists. We treated with PK2 immune cells activated against myelin antigen to explore the immune-modulating effects of this peptide in vitro.
  
  
  RESULTS
  Pk2 messenger RNA was upregulated in spinal cord and lymph node cells (LNCs) of mice with EAE. PK2 protein was expressed in EAE inflammatory infiltrates and was increased in sera during EAE. In patients with relapsing-remitting MS, transcripts for PK2 were significantly increased in peripheral blood mononuclear cells compared with healthy controls, and PK2 serum concentrations were significantly higher. A PK2 receptor antagonist prevented or attenuated established EAE in chronic and relapsing-remitting models, reduced CNS inflammation and demyelination, and decreased the production of interferon (IFN)-γ and interleukin (IL)-17A cytokines in LNCs while increasing IL-10. PK2 in vitro increased IFN-γ and IL-17A and reduced IL-10 in splenocytes activated against myelin antigen.
  
  
  CONCLUSIONS
  These data suggest that PK2 is a critical immune regulator in CNS autoimmune demyelination and may represent a new target for therapy.
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Mhamad
authors.initials: M
authors.lastname: Abou-Hamdan
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Costanza
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Elena
authors.initials: E
authors.lastname: Fontana
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Marco
authors.initials: M
authors.lastname: Di Dario
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Musio
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Cenzo
authors.initials: C
authors.lastname: Congiu
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Onnis
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lattanzi
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Marta
authors.initials: M
authors.lastname: Radaelli
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Martinelli
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Negri
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Cinthia
authors.initials: C
authors.lastname: Farina
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA.
authors.forename: Rosetta
authors.initials: R
authors.lastname: Pedotti