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.
|Titolo:||Exposure to a dysfunctional GR from early embryonic life programs the resistance to experimental autoimmune encephalomyelitis via NO-induced immunosuppression. J. Immunology|
|Data di pubblicazione:||2002|
|Citazione:||Exposure to a dysfunctional GR from early embryonic life programs the resistance to experimental autoimmune encephalomyelitis via NO-induced immunosuppression. J. Immunology / MARCHETTI B; MORALE MC; BROUWER J; TIROLO C; TESTA N; CANIGLIA S; BARDEN N; AMOR S; SMITH PA; DIJKISTRA CD.. - In: JOURNAL OF IMMUNOLOGY. - ISSN 0022-1767. - 168:11(2002), pp. 5848-5859.|
|Appare nelle tipologie:||1.1 Articolo in rivista|