Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis
Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis
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DOI：
10.1038/nature05590
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发表时间：
2007-03-29
期刊：
影响因子：
64.8
通讯作者：
Artis, David
中科院分区：
文献类型：
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作者：
Zaph, Colby;Troy, Amy E.;Artis, David
肠上皮细胞（IEC）提供了一个主要的物理屏障，以抵御胃肠道（GI）中的寄生虫和病原微生物，但IEC对感染免疫力的发展和调节的影响尚不清楚（1）。在这里，我们表明IEC-内在I κ B激酶（IKK）-β依赖性基因表达是胃肠道中树突状细胞和CD 4（+）T细胞反应的关键调节因子。IEC特异性IKK-β缺失的小鼠表现出肠内上皮细胞限制性细胞因子胸腺基质淋巴细胞生成素的表达减少，并且在感染肠道寄生虫鞭虫后，不能产生病原体特异性CD 4（+）T辅助2型（T（H）2）应答，并且不能根除感染。此外，这些动物表现出树突细胞衍生的白细胞介素-12/23 p40和肿瘤坏死因子-α的产生加剧，CD 4（+）T细胞衍生的干扰素-γ和白细胞介素-17的水平增加，并发生严重的肠道炎症。鞭虫感染期间促炎细胞因子的阻断消除了IEC对IKK-β的需求，以促进CD 4（+）T（H）2细胞依赖性免疫，确定了IEC在树突状细胞的组织特异性调节中的基本功能，并限制了胃肠道中1型细胞因子的产生。这些结果表明，IKK-β依赖性基因在肠上皮细胞中的表达的平衡是至关重要的肠道免疫稳态，通过促进粘膜免疫和限制慢性炎症。
Intestinal epithelial cells ( IECs) provide a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestinal ( GI) tract, but the influence of IECs on the development and regulation of immunity to infection is unknown(1). Here we show that IEC-intrinsic I kappa B kinase ( IKK)-beta-dependent gene expression is a critical regulator of responses of dendritic cells and CD4(+) T cells in the GI tract. Mice with an IEC-specific deletion of IKK-beta show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4(+) T helper type 2 (T(H)2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-alpha, increased levels of CD4(+) T-cell-derived interferon-gamma and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-beta in IECs to promote CD4(+) T(H)2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the GI tract. These results indicate that the balance of IKK-beta-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.