NITRIC-OXIDE ACCELERATES THE ONSET AND INCREASES THE SEVERITY OF EXPERIMENTAL AUTOIMMUNE UVEORETINITIS THROUGH AN IFN-GAMMA-DEPENDENT MECHANISM

The production of large amounts of nitric oxide (NO) by inducible nitr ic oxide synthase (iNOS) has been described as a double-edged sword el iciting pro-or anti-inflammatory effects in different immune situation s, Our aim, therefore, was to investigate its role in experimental aut oimmune uveoretinitis (EAU), a model of ocular inflammation, induced i n the Lewis rat following a single footpad injection of retinal Ags. i NOS enzyme was not detected in the normal Lewis rat eye, but was stron gly expressed by infiltrating ED1(+) macrophages during the acute infl ammatory stages of EAU, Treating immunized animals with L-arginine inc reased urinary NO metabolite (NOx) levels, accelerated the inflammator y response, and increased disease severity, whereas treatment with the NOS inhibitor, N-G-nitro-L-arginine methyl ester, reduced NOx excreti on, delayed the onset, and reduced the clinical signs of EAU, Reverse transcription-PCR analysis of ocular tissue from untreated and treated animals detected iNOS mRNA at all stages of disease, and expression w as up-regulated during peak disease, L-arginine treatment enhanced cyt okine mRNA expression, particularly of IFN-gamma, which was detected e arlier than in control animals, corresponding with the more rapid onse t of disease and increased disease severity observed in this group. N- G-nitro-L-arginine methyl ester had little or no effect on iNOS or inf lammatory cytokine mRNA expression, These results suggest NO is centra l to the pathogenesis of EAU and highlight the importance of the macro phage as an effector cell in what is considered a CD4(+) T cell-depend ent disease, Furthermore, this study demonstrates the therapeutic pote ntial of NOS inhibitors in the treatment of inflammatory and autoimmun e mediated disease.