J Immunol 2002 Jun 1;168(11):5848-5859
Marchetti B, Morale MC, Brouwer J, Tirolo C, Testa N, Caniglia S, Barden N, Amor S, Smith PA, Dijkstra CD.
Department of Pharmacology, University of Sassari Medical School, Sassari, Italy. Neuropharmacology, OASI Institute for Research and Care on Mental Retardation and Brain Aging, Troina, Italy. Molecular Cell Biology, Vrije Universiteit Medical Center, Van der Boechorststraat, Amsterdam, The Netherlands. Centre Hospitalier de l'Universite Laval Research Center and Department of Anatomy and Physiology, Laval University, Quebec, Canada. Department of Neuroinflammation, Division of Neurosciences, Imperial College School of Medicine, London, United Kingdom. Department of Immunobiology, Biomedical Primate Research Center, Rijswijk, The Netherlands.
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.