Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease.
Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease.
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DOI：
10.1084/jem.20020281
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发表时间：
2002-12-16
期刊：
影响因子：
--
通讯作者：
Kollias G
中科院分区：
文献类型：
--
作者：
Kontoyiannis D;Boulougouris G;Manoloukos M;Armaka M;Apostolaki M;Pizarro T;Kotlyarov A;Forster I;Flavell R;Gaestel M;Tsichlis P;Cominelli F;Kollias G
最近的临床证据表明，肿瘤坏死因子在克罗恩病的发生发展中起着重要作用。以前已经通过在翻译控制肿瘤坏死因子基因(ΔAREmouse)中的工程缺陷建立了这种病理的小鼠模型。在这里，我们表明，在这个模型中，肠道病理的发展依赖于Th1型细胞因子，如白细胞介素12和干扰素γ，并需要CD8+T淋巴细胞的功能。通过Cre/loxP介导的重组对突变的肿瘤坏死因子等位基因的组织特异性激活，表明髓系或T细胞来源的肿瘤坏死因子都可以表现出完全的致病能力。此外，使用肿瘤坏死因子受体缺陷小鼠进行的相互骨髓移植实验表明，当肿瘤坏死因子信号独立定向到骨髓来源的细胞或组织基质细胞靶点时，同样具有致病性。有趣的是，在缺乏MAPKAP激酶2的情况下，肿瘤坏死因子介导的肠道病理会加剧，而在Cot/Tpl2或JNK2激酶缺乏的遗传背景下，肿瘤坏死因子介导的肠道病理会显著减弱。我们的数据证实了炎症性肠病中在肿瘤坏死因子下游操作的多余细胞通路的存在，并证明了选择性激酶阻断在肿瘤坏死因子介导的肠道病理中的治疗潜力。
Recent clinical evidence demonstrated the importance of tumor necrosis factor (TNF) in the development of Crohn's disease. A mouse model for this pathology has previously been established by engineering defects in the translational control of TNF mRNA (Tnf Δ AREmouse). Here, we show that development of intestinal pathology in this model depends on Th1-like cytokines such as interleukin 12 and interferon γ and requires the function of CD8+ T lymphocytes. Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell–derived TNF can exhibit full pathogenic capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF receptor–deficient mice revealed that TNF signals are equally pathogenic when directed independently to either bone marrow–derived or tissue stroma cell targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase–deficient genetic background. Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.
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影响因子：
32.4
作者：
Kontoyiannis, D;Pasparakis, M;Kollias, G
通讯作者：
Kollias, G
影响因子：
64.8
作者：
Belich, MP;Salmerón, A;Ley, SC
通讯作者：
Ley, SC
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
64.5
作者：
ITOHARA, S;MOMBAERTS, P;TONEGAWA, S
通讯作者：
TONEGAWA, S
影响因子：
11.4
作者：
Kontoyiannis, D;Kotlyarov, A;Kollias, G
通讯作者：
Kollias, G