Helicobacter hepaticus-induced colitis in interleukin-10-deficient mice:: Cytokine requirements for the induction and maintenance of intestinal inflammation
Helicobacter hepaticus-induced colitis in interleukin-10-deficient mice:: Cytokine requirements for the induction and maintenance of intestinal inflammation
复制标题
DOI：
10.1128/iai.69.7.4232-4241.2001
复制
发表时间：
2001-07-01
影响因子：
3.1
通讯作者：
Sher, A
中科院分区：
文献类型：
--
作者：
Kullberg, MC;Rothfuchs, AG;Sher, A
我们以前已经表明，特异性病原体的无白细胞介素-10（IL-10）缺陷（IL-10 KO）与肝螺杆菌重建小鼠发展严重的结肠炎与Th 1型细胞因子的反应。在本研究中，我们正式证明IL-12对于疾病诱导至关重要，因为IL-10和IL-12 p40缺陷的小鼠在肝血吸虫感染后没有表现出肠道病理学。通过使用针对IL-12、γ干扰素（IFN-γ）和肿瘤坏死因子α（TNF-α）的单克隆抗体（MAbs），我们进一步分析了这些细胞因子在具有已建立的H.肝源性结肠炎用抗IL-12 p40治疗感染的结肠炎IL-10 KO小鼠导致肠道炎症、结肠IFN-γ、TNF-α和诱导型一氧化氮合酶（iNOS）mRNA水平以及肠系膜淋巴结（MLN）细胞分泌的H、肝特异性IFN-γ与对照MAb治疗小鼠中的发现相比显著降低。此外，病理学的减轻与结肠CD 3（+）T细胞数量的减少和MLN中螺杆菌反应性CD 4（+）Th 1细胞频率的显著降低有关。相反，抗IFN-γ和/或抗TNF-α对患有结肠炎的IL-10 KO小鼠的肠道炎症没有影响。我们进一步表明IFN-γ不是肝吸虫感染后结肠炎发展所必需的。来自感染的IL-10/IFN-γ KO动物的MLN细胞在细菌抗原刺激后分泌升高量的IL-12和TNF-α，表明疾病诱导的替代途径。综上所述，我们的研究结果表明，IL-12在诱导和维持肠道炎症通过募集和维持一个池的致病性Th 1细胞的关键作用。
We have previously shown that specific-pathogen-free interleukin-10 (IL-10)-deficient (IL-10 KO) mice reconstituted with Helicobacter hepaticus develop severe colitis associated with a Th1-type cytokine response. In the present study, we formally demonstrate that IL-12 is crucial for disease induction, because mice deficient for both IL-10 and IL-12 p40 show no intestinal pathology following H, hepaticus infection. By using monoclonal antibodies (MAbs) to IL-12, gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha), we have further analyzed the role of these cytokines in the maintenance of the Th1 response and inflammation in IL-10 KO mice with established H. hepaticus-induced colitis. Treatment of infected colitic IL-10 KO mice with anti-IL-12 p40 resulted in markedly reduced intestinal inflammation, colonic IFN-gamma, TNF-alpha, and inducible nitric oxide synthase (iNOS) mRNA levels, and H, hepaticus-specific IFN-gamma secretion by mesenteric lymph node (MLN) cells compared to the findings in control MAb-treated mice. Moreover, the diminished pathology was associated with decreased numbers of colonic CD3(+) T cells and significantly reduced frequencies of Helicobacter-reactive CD4(+) Th1 cells in MLN, In contrast, anti-IFN-gamma and/or anti-TNF-alpha had no effect on intestinal inflammation in IL-IO KO mice with established colitis, Using IL-10/IFN-gamma double-deficient mice, we further show that IFN-gamma is not required for the development of colitis following H, hepaticus infection. MLN cells from infected IL-10/IFN-gamma KO animals secreted elevated amounts of IL-12 and TNF-alpha following bacterial antigen stimulation, indicating alternative pathways of disease induction. Taken together, our results demonstrate a crucial role for IL-12 in both inducing and sustaining intestinal inflammation through recruitment and maintenance of a pool of pathogenic Th1 cells.