title: Nitric oxide inhibits CXCL12 expression in neuroinflammation.
abstract: Chemokine CXCL12 (C-X-C motif chemokine ligand 12) restricts immune cell invasion of the central nervous system (CNS) and limits neuroinflammation in experimental autoimmune encephalomyelitis (EAE), an animal model of inflammatory and demyelinating disease of the CNS, multiple sclerosis (MS). Nitric oxide (NO), by contrast, predominantly contributes to CNS tissue destruction in MS and EAE. Thus, the influence of NO on CXCL12 in the inflamed CNS was investigated. Excess expression of inducible NO synthase was inversely correlated to CXCL12 gene expression in spinal cord homogenates of rats immunized to develop EAE. NO inhibited gene expression of CXCL12 in astrocytes and endothelial cells in vitro. The inhibition was paralleled with reduction of p38 mitogen-activated protein kinase (MAPK) phosphorylation and it was mimicked with inhibitors of p38 MAPK activation in astrocytes. In vivo suppression of nitric generation recovered CXCL12 expression in the CNS and attenuated EAE in Dark Agouti rats. On the contrary, in vivo NO donation decreased CXCL12 expression in the CNS of EAE-resistant Albino Oxford (AO) rats. However, the effect was not paralleled with induction of EAE in AO rats. It is suggested that NO acting through suppression of p38 MAPK inhibits CXCL12 expression in neuroinflammation. These results imply that downregulation of NO release and protection of CXCL12 expression within the CNS might present the potential approaches in MS therapy.
authors.affiliation: Department of Immunology, Institute for Biological Research, Siniša Stanković, University of Belgrade, Belgrade, Serbia.
authors.forename: Filip
authors.initials: F
authors.lastname: Petković
authors.forename: Jana
authors.initials: J
authors.lastname: Blaževski
authors.forename: Miljana
authors.initials: M
authors.lastname: Momčilović
authors.forename: Marija
authors.initials: M
authors.lastname: Mostarica Stojkovic
authors.forename: Djordje
authors.initials: D
authors.lastname: Miljković
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000628:therapy; D042783:Endothelial Cells / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods / Q000639:trends; D009103:Multiple Sclerosis / Q000276:immunology* / Q000628:therapy; D009569:Nitric Oxide / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases