Mice with an inactivation of the inducible nitric oxide synthase gene are susceptible to experimental autoimmune encephalomyelitis

Nitric oxide (NO) generated by the inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study mice genetically deficient for iNOS are shown to be susceptible to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG). In iNOS (–/–) mice the course of disease was earlier in onset and more aggressive compared to control animals. A disease‐relevant compensatory up‐regulation of neuronal (n)NOS and endothelial (e)NOS with increased production of NO in iNOS (–/–) mice is excluded by 1) the failure to detect increased nNOS and eNOS mRNA, 2) the absence of detection of nitrosylated tyrosine residues in EAE tissue indicating absence of NO‐derived peroxynitrite, and 3) the lack of disease‐preventing effects of NG‐nitro‐L‐arginine methylester. In conclusion, these results do not support the hypothesis that NO is crucial for the development of EAE.

[1]  M. Watson,et al.  Expression , 2003, The Oxford Handbook of Western Music and Philosophy.

[2]  A. Cross,et al.  Evidence for the production of peroxynitrite in inflammatory CNS demyelination , 1997, Journal of Neuroimmunology.

[3]  Hans Lassmann,et al.  T-cell apoptosis in autoimmune diseases: termination of inf lammation in the nervous system and other sites with specialized immune-defense mechanisms , 1997, Trends in Neurosciences.

[4]  J. Pittner,et al.  Increased blood pressure in rats after long-term inhibition of the neuronal isoform of nitric oxide synthase. , 1997, The Journal of clinical investigation.

[5]  R. Sobel,et al.  Inhibition of nitric oxide synthase for treatment of experimental autoimmune encephalomyelitis. , 1997, Journal of immunology.

[6]  A. Cross,et al.  Inducible nitric oxide synthase gene expression and enzyme activity correlate with disease activity in murine experimental autoimmune encephalomyelitis , 1996, Journal of Neuroimmunology.

[7]  W. Wilkinson,et al.  Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients , 1996, The Journal of experimental medicine.

[8]  S. Linden,et al.  Aggravation of experimental allergic encephalomyelitis (EAE) by administration of nitric oxide (NO) synthase inhibitors , 1996, Clinical and experimental immunology.

[9]  M. Mcdaniel,et al.  Experimental allergic encephalomyelitis in the rat is inhibited by aminoguanidine, an inhibitor of nitric oxide synthase , 1996, Journal of Neuroimmunology.

[10]  H. Wong,et al.  Peroxynitrite-mediated DNA strand breakage activates poly-adenosine diphosphate ribosyl synthetase and causes cellular energy depletion in macrophages stimulated with bacterial lipopolysaccharide. , 1996, Journal of immunology.

[11]  S. Sakoda,et al.  Expression of the inducible isoform of nitric oxide synthase in the central nervous system of mice correlates with the severity of actively induced experimental allergic encephalomyelitis , 1995, Journal of Neuroimmunology.

[12]  A. Ben-nun,et al.  A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H‐2b mice: Fine specificity and T cell receptor Vβ expression of encephalitogenic T cells , 1995, European journal of immunology.

[13]  K. Frei,et al.  Production of nitrite by primary rat astrocytes in response to pneumococci , 1995, Journal of Neuroimmunology.

[14]  C. Nathan,et al.  Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase , 1995, Cell.

[15]  H. Hartung,et al.  Administration of nitric oxide synthase inhibitors in experimental autoimmune neuritis and experimental autoimmune encephalomyelitis , 1995, Journal of Neuroimmunology.

[16]  A. Cross,et al.  Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. , 1994, The Journal of clinical investigation.

[17]  I. Charles,et al.  Induction of calcium-dependent nitric oxide synthases by sex hormones. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. Nathan,et al.  Regulation of biosynthesis of nitric oxide. , 1994, The Journal of biological chemistry.

[19]  S Moncada,et al.  Nitric oxide synthases in mammals. , 1994, The Biochemical journal.

[20]  M. Seldin,et al.  The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L- arginine , 1994, The Journal of experimental medicine.

[21]  L. Ignarro,et al.  Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. , 1993, Journal of immunology.

[22]  J S Beckman,et al.  Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. , 1992, Archives of biochemistry and biophysics.

[23]  D. Peterson,et al.  The non specificity of specific nitric oxide synthase inhibitors. , 1992, Biochemical and biophysical research communications.

[24]  C. Nathan,et al.  Nitric oxide and macrophage function. , 1997, Annual review of immunology.

[25]  H. Mcdevitt,et al.  Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. , 1995, Immunology today.

[26]  H. McFarland,et al.  Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. , 1995, Critical reviews in clinical laboratory sciences.

[27]  A. MacKenzie-Graham,et al.  Differential sensitivity to nitric oxide in immortalized, cloned murine oligodendrocyte cell lines. , 1994, Developmental neuroscience.