An influence of granulocyte colony-stimulating factor upon pathogenesis of inflammatory bowel disease

炎症性肠病（IBD）不是一个单一的实体，而是一个连续的疾病谱系。虽然Th1免疫与克罗恩病（CD）的发病有关，但粘膜内中性粒细胞浸润与溃疡性结肠炎（UC）的活动有关。我们发现不同品系大鼠粒细胞集落刺激因子（G-CSF）的表达量存在明显差异，其中SD和DA大鼠lps刺激的脾细胞内源性G-CSF mRNA表达量明显低于Lewis、F344和BN大鼠。我们检测了重组G-CSF对五种大鼠菌株TNBS（半抗原）诱导的两种类型结肠炎的治疗效果。肛门注射TNBS后第7天，SD和DA表现为大量淋巴细胞浸润，IFN-γ mRNA上调（cd样结肠炎），而Lewis、F344和BN表现为强烈的粘膜下中性粒细胞积累，TNF-α mRNA水平高（uc样结肠炎）。重组G-CSF预处理5天，多剂量t （250μg/kg/天，s.c）降低了这两种细胞因子的升高水平。该处理提高了DA的存活率，降低了SD的体重减轻程度，而对其他菌株的体重减轻没有显著影响。重组G-CSF处理后第1天，F344中性粒细胞为主的病变中IL-10 mRNA水平高度上调，而SD的th1型病变中IL-12p35 mRNA水平均下调。在内源性G-CSF表达较高的宿主中，G-CSF的供应可防止th1型结肠炎的发生，并且不会恶化中性粒细胞为主的慢性结肠炎。我们试图阐明G-CSF产率对IBD发病机制的影响，以分析手术人体标本，但本研究期间样本量不足。通过合成G-CSF和IL-10融合蛋白开发抗炎新药，任何合成蛋白对体外lps刺激的人白细胞IL-12分泌的抑制作用在单位摩尔基础上均不明显高于IL-10。在这个项目的预算下，我们没有获得足够的合成蛋白质的体积来测量它们在体内的半衰期。少

Inflammatory bowel disease (IBD) is not a single entity but represents a continuous spectrum of disease. While Th1 immunity is responsible for the onset of Crohn's disease (CD), intramucosal neutrophil infiltration is related to the activity of ulcerative colitis (UC). We found that there is distinct difference in the productivity of granulocyte colony-stimulating factor (G-CSF) among rat strains, in which SD and DA rats showed much lower mRNA expression levels of endogenous G-CSF in LPS-stimulated splenocytes than did Lewis, F344 and BN rats. We examined the therapeutic effects of recombinant G-CSF in the two types of TNBS (a hapten)-induced colitis of five rat strains. On day 7 after anal instillation of TNBS, SD and DA demonstrated massive lymphocyte infiltration with an IFN-γ mRNA upregulation (CD-like colitis), while Lewis, F344 and BN showed an intense submucosal neutrophil accumulation with high TNF-α mRNA levels (UC-like colitis). A 5-day course of recombinant G-CSF pretreatmen … More t (250μg/kg/day, s.c.) reduced the elevated levels of the both cytokines. The treatment improved the survival rate of DA and reduced the degree of body weight loss of SD, while not significantly influencing the weight loss of other strains. IL-10 mRNA levels were highly upregulated by recombinant G-CSF treatment on day 1 in the neutrophil-dominant lesions of F344 but not in the Th1-type lesions of SD, and IL-12p35 mRNA levels were downregulated in the both. Supply of G-CSF prevents the onset of Th1-type colitis and does not deteriorate neutrophil-dominant chronic colitis in the hosts showing higher expression of endogenous G-CSF. We tried to elucidate the influence of G-CSF productivity on the pathogenesis of IBD to analyze surgical human specimen, but the sample size was insufficient within the period of this study. As for development of new anti-inflammatory drugs by synthesizing fusion proteins of G-CSF and IL-10, any synthesized proteins did not show much more inhibition of IL-12 secretion by in vitro LPS-stimulated human leukocytes than IL-10 on a per-mol basis. We did not obtain enough volume of the synthesized proteins to measure their half-life time in vivo with the budget of this project. Less