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

粒细胞集落刺激因子对炎症性肠病发病机制的影响

基本信息

批准号：
16591320
负责人：
HAYAMIZU Keisuke
金额：
$ 2.11万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591320/
关键词：
inflammatory bowel disease Crohn's disease ulcerative colitis G-CSF IL-12 TNBS-induced colitis IL-10 融合蛋白 STAT3 創薬自己免疫疾患

项目摘要

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

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。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的浸润与溃疡性结肠炎(UC)的活动性有关。我们发现不同品系的大鼠产生粒细胞集落刺激因子(G-CSF)的能力存在明显差异，其中SD和DA大鼠的内源性G-CSFmRNA表达水平明显低于Lewis、F344和BN大鼠。我们观察了重组G-CSF对两种类型的TNBS(一种半抗原)诱导的5个品系大鼠结肠炎的治疗作用。在灌胃TNBS后第7天，SD组和DA组可见大量淋巴细胞浸润并伴有干扰素-γ基因表达上调(CD样结肠炎)，而Lewis、F344和BN组则表现为粘膜下中性粒细胞大量聚集并高水平表达肿瘤坏死因子-α(UC样结肠炎)。重组人粒细胞集落刺激因子预处理…的5天疗程更多t(250μg/kg/天，S.C.)降低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的体重损失程度，而对其他品系的体重损失没有显著影响。重组G-CSF治疗后第1天，中性粒细胞占优势的F344皮损中IL-10mRNA表达显著上调，而Th1型SD皮损中IL-12p35mRNA表达下调。补充G-CSF可预防Th1型结肠炎的发生，并且不会加重内源性G-CSF高表达的宿主中性粒细胞占优势的慢性结肠炎。我们试图通过对手术标本的分析来阐明G-CSF的产生对IBD发病机制的影响，但在本研究期间样本量不足。至于通过合成G-CSF和IL-10的融合蛋白来开发新的抗炎药物，任何合成的蛋白对体外培养的人白细胞分泌IL-12的抑制程度并不比每摩尔的IL-10大。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。较少