Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis
Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis
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DOI：
10.1016/j.immuni.2006.06.018
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发表时间：
2006-09-01
期刊：
影响因子：
32.4
通讯作者：
Strober, Warren
中科院分区：
文献类型：
--
作者：
Watanabe, Tomohiro;Kitani, Atsushi;Strober, Warren
在这项研究中，我们确定了导致核苷酸结合寡聚结构域2 （NOD2）缺陷小鼠结肠炎发展的条件，NOD2是克罗恩病的一个易感性因素。我们发现nod2缺陷抗原呈递细胞（APCs）在存在卵清蛋白（OVA）肽和肽聚糖或表达OVA肽（ECOVA）的重组大肠杆菌的情况下产生增加的白细胞介素(IL)-12。此外，这些apc在共培养的ova特异性CD4(+) T细胞中引起干扰素- γ (ifn - γ)反应增强。然后，我们证明了nod2缺陷小鼠过性转移ova特异性CD4(+) T细胞，并且直肠内给予ECOVA的小鼠发生结肠炎，结肠炎与ova特异性CD4(+) T细胞扩增产生ifn - γ相关。重要的是，这种结肠炎高度依赖toll样受体2 （TLR2）功能，因为它在NOD2和TLR2双缺陷小鼠中被抑制。因此，当有能力对粘膜细菌表达的抗原作出反应时，nod2缺陷小鼠由于TLR2反应增加而易患结肠炎。
In this study, we determined conditions leading to the development of colitis in mice with nucleotide binding oligomerization domain 2 (NOD2) deficiency, a susceptibility factor in Crohn's disease. We found that NOD2-deficient antigen-presenting cells (APCs) produced increased amounts of interleukin (IL)-12 in the presence of ovalbumin (OVA) peptide and peptidoglycan or recombinant E. coli that express OVA peptide (ECOVA). Furthermore, these APCs elicited heightened interferon-gamma (IFN-gamma) responses from cocultured OVA-specific CD4(+) T cells. We then demonstrated that NOD2-deficient mice adoptively transferred OVA-specific CD4(+) T cells and that administered intrarectal ECOVA developed colitis associated with the expansion of OVA-specific CD4(+) T cells producing IFN-gamma. Importantly, this colitis was highly dependent on Toll-like receptor 2 (TLR2) function since it was suppressed in NOD2 and TLR2 double-deficient mice. Thus, NOD2-deficient mice become susceptible to colitis as a result of increased TLR2 responses when they have the capacity to respond to an antigen expressed by mucosal bacteria.