Bertrand V, Quéré S, Guimbaud R, Sogni P, Chauvelot-Moachon L, Tulliez M, Lamarque D, Charreire J, Giroud J P, Couturier D, Chaussade S, Breban M
Groupe de Recherche en Pathologie Digestive, Hôpital Cochin, Paris, France.
Eur Cytokine Netw. 1998 Jun;9(2):161-70.
Rats transgenic for HLA-B27 and human beta 2-microglobulin develop a spontaneous, multisystem, inflammatory disease that resembles human B27-associated disease and that involves the gut mucosa. This model predominantly affects the colon and is characterized by an extensive infiltration of the mucosa by inflammatory cells, largely composed of mononuclear cells. In 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 development of colitis in IL-10 knockout mice, suggesting that IL-10 plays a major role in the control of gut inflammation. The objectives of this 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 disease 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 (myeloperoxidase and inducible NO synthase activities; tumor necrosis factor-alpha, interferon-delta, CD3, iNOS and beta-actin mRNA expression. In 33-3 rats with established disease, mesenteric lymph nodes were hyperplastic, and colonic cellularity and MPO and iNOS activities in the colonic mucosa were increased without any detectable effects of IL-10 administration. IFN-gamma and iNOS mRNA were only detected in the colon of transgenic rats. Despite a lack of effect on disease expression, IL-10 strikingly reduced the level of IFN-gamma mRNA in gut mucosa. Up-regulation of IFN-gamma mRNA suggests that the IBD of HLA-B27 rats is mediated by T-helper 1 lymphocytes. Sustained administration of IL-10, in HLA-B27 rats with established disease, efficiently inhibited IFN-gamma mRNA 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.
携带HLA - B27和人β2 - 微球蛋白的转基因大鼠会自发患上一种多系统炎症性疾病，该疾病类似于人类B27相关疾病，且累及肠道黏膜。此模型主要影响结肠，其特征是炎症细胞大量浸润黏膜，这些炎症细胞主要由单核细胞组成。此外，该模型中还出现血浆中一氧化氮（NO）衍生代谢产物水平升高的情况。抗炎细胞因子白细胞介素 - 10（IL - 10）缺乏会导致IL - 10基因敲除小鼠发生结肠炎，这表明IL - 10在控制肠道炎症中起主要作用。本研究的目的是探讨HLA - B27大鼠炎症性肠病（IBD）的发病机制，并确定IL - 10治疗的效果。在两个连续实验中，用小鼠重组IL - 10对已患疾病的HLA - B27重组大鼠33 - 3品系进行了为期五周的治疗。基于临床、组织学和生物学指标（髓过氧化物酶和诱导型一氧化氮合酶活性；肿瘤坏死因子 - α、干扰素 - δ、CD3、诱导型一氧化氮合酶和β - 肌动蛋白mRNA表达）对该治疗效果进行了评估。在已患疾病的33 - 3大鼠中，肠系膜淋巴结增生，结肠黏膜中的细胞数量以及MPO和iNOS活性增加，而给予IL - 10未产生任何可检测到的效果。仅在转基因大鼠的结肠中检测到IFN - γ和iNOS mRNA。尽管对疾病表现没有影响，但IL - 10显著降低了肠道黏膜中IFN - γ mRNA的水平。IFN - γ mRNA的上调表明HLA - B27大鼠的IBD是由辅助性T1淋巴细胞介导的。在已患疾病的HLA - B27大鼠中持续给予IL - 10可有效抑制IFN - γ mRNA表达，但不影响疾病表现：这些结果表明，IFN - γ可能在疾病的早期阶段而非病变维持阶段发挥关键作用。
