title: Exposure to a dysfunctional glucocorticoid receptor from early embryonic life programs the resistance to experimental autoimmune encephalomyelitis via nitric oxide-induced immunosuppression.
abstract: Glucocorticoid (GC) hormones play a central role in the bidirectional communication between the neuroendocrine and the immune systems and exert, via GC receptors (GR), potent immunosuppressive and anti-inflammatory effects. In this study, we report that GR deficiency of transgenic mice expressing GR antisense RNA from early embryonic life has a dramatic impact in programming the susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. GR deficiency renders mice resistant to myelin oligodendrocyte glycoprotein-induced EAE, and such mice do not develop clinical or histological signs of disease compared with EAE-susceptible wild-type mice. Resistance to EAE in GR-deficient mice is associated not with endogenous GC levels, but with a significant reduction in spleen and lymph node cell proliferation. The use of NO inhibitors in vitro indicates that NO is the candidate immunosuppressor molecule. GR-deficient mice develop 3- to 6-fold higher nitrite levels in the periphery and are resistant to NO inhibition by GCs. Specific inhibition of NO production in vivo by treatment with the inducible NO synthase inhibitor, L-N(6)-(1-iminoethyl)-lysine, suppressed circulating nitrites, increased myelin oligodendrocyte glycoprotein-specific cell proliferation, and rendered GR-deficient mice susceptible to EAE. Thus, life-long GR deficiency triggers inducible NO synthase induction and NO generation with consequent down-regulation of effector cell proliferation. These findings identify a novel link among GR, NO, and EAE susceptibility and highlight NO as critical signaling molecule in bidirectional communication between the hypothalamic-pituitary-adrenocortical axis and the immune system.
authors.affiliation: Department of Pharmacology, University of Sassari Medical School, Sassari, Italy. bianca.marchetti@oasi.en.it
authors.forename: Bianca
authors.initials: B
authors.lastname: Marchetti
authors.forename: Maria C
authors.initials: MC
authors.lastname: Morale
authors.forename: Jantien
authors.initials: J
authors.lastname: Brouwer
authors.forename: Cataldo
authors.initials: C
authors.lastname: Tirolo
authors.forename: Nuccio
authors.initials: N
authors.lastname: Testa
authors.forename: Salvo
authors.initials: S
authors.lastname: Caniglia
authors.forename: Nicholas
authors.initials: N
authors.lastname: Barden
authors.forename: Sandra
authors.initials: S
authors.lastname: Amor
authors.forename: Paul A
authors.initials: PA
authors.lastname: Smith
authors.forename: Christine D
authors.initials: CD
authors.lastname: Dijkstra
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000097:blood; D004622:Embryo, Mammalian / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D007108:Immune Tolerance; D007114:Immunization; D008213:Lymphocyte Activation; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D011965:Receptors, Glucocorticoid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D003345:Corticosterone