EFFECTS OF MURINE RECOMBINANT INTERLEUKIN-10 ON THE INFLAMMATORY DISEASE OF RATS TRANSGENIC FOR HLA-B27 AND HUMAN BETA-2-MICROGLOBULIN

Rats transgenic for HLA-B27 and human beta 2-microglobulin develop a s pontaneous, multisystem, inflammatory disease that resembles human B27 -associated disease and that involves the gut mucosa, This model predo minantly affects the colon and is characterized by an extensive infilt ration of the mucosa by inflammatory cells, largely composed of mononu clear cells. Ire addition, an increased plasma level of nitric oxide ( NO)-derived metabolites was described in this model, Deficiency in the anti-inflammatory cytokine, interleukin-10 (IL-10), leads to the deve lopment of colitis in IL-10 knockout mice, suggesting that IL-10 plays a major role in the control of gut inflammation. The objectives of th is work were to study the mechanisms of the inflammatory bowel disease (IBD) in HLA-B27 rats and to determine the effects of treatment with IL-10, The 33-3 line of HLA-B27 recombinant rats with established dise ase was treated in two consecutive experiments with murine recombinant IL-10 for five weeks. Assessment of the effect of this treatment was performed, based on clinical, histological and biological (myeloperoxi dase and inducible NO synthase activities; tumor necrosis factor-alpha , interferon-gamma, CD3, iNOS and beta-actin mRNA expression. In 33-3 rats with established disease, mesenteric lymph nodes were hyperplasti c, and colonic cellularity and MPO and iNOS activities in the colonic mucosa were increased without any detectable effects of IL-10 administ ration. IFN-gamma and iNOS mRNA were only detected in the colon of tra nsgenic rats. Despite a lack of effect on disease expression, IL-10 st rikingly reduced the level of IFN-gamma mRNA in gut mucosa, Up-regulat ion of IFN-gamma mRNA suggests that the IBD of HLA-B27 rats is mediate d by T-helper 1 lymphocytes, Sustained administration of IL-10, in HLA -B27 rats with established disease, efficiently inhibited IFN-gamma mR NA expression but did not influence disease expression: these results indicate that IFN-gamma may exert a critical role at an earlier stage of the disease rather in the maintenance of the lesions.