TNFAIP3 maintains intestinal barrier function and supports epithelial cell tight junctions.
TNFAIP3 maintains intestinal barrier function and supports epithelial cell tight junctions.
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DOI：
10.1371/journal.pone.0026352
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Boone DL
中科院分区：
文献类型：
--
作者：
Kolodziej LE;Lodolce JP;Chang JE;Schneider JR;Grimm WA;Bartulis SJ;Zhu X;Messer JS;Murphy SF;Reddy N;Turner JR;Boone DL
肠上皮细胞之间的紧密连接介导肠屏障的渗透性，并且由TNF信号传导介导的肠屏障功能的丧失与克罗恩病和乳糜泻中观察到的炎性病理生理学相关。因此，调节肠上皮细胞对TNF的反应的因素可能对屏障功能的维持至关重要。TNF α诱导蛋白3（TNFAIP 3）是一种细胞溶质蛋白，其在负反馈环中起作用以调节由Toll样受体配体和TNF诱导的细胞信号传导，表明TNFAIP 3可能在调节肠屏障中起作用。为了研究TNFAIP 3在肠屏障功能中的特定作用，我们评估了TNFAIP 3 −/−小鼠和LPS处理的villin-TNFAIP 3转基因小鼠的屏障通透性。与野生型同窝仔相比，TNFAIP 3 −/−小鼠具有更大的肠道通透性，而villin-TNFAIP 3转基因小鼠受到LPS处理的野生型同窝仔中观察到的通透性增加的保护，表明屏障通透性由TNFAIP 3控制。在培养的人肠上皮细胞系中，TNFAIP 3表达调节TNF诱导和肌球蛋白轻链激酶调节的紧密连接动力学，但不影响肌球蛋白轻链激酶活性。小鼠肠的免疫组织化学显示TNFAIP 3表达抑制LPS诱导的肠上皮顶端边缘紧密连接蛋白occludin的丢失。我们还发现TNFAIP 3去泛素化聚泛素化闭合蛋白。这些体内和体外研究支持TNFAIP 3在促进肠上皮屏障完整性中的作用，并证明其通过紧密连接蛋白调节维持肠内稳态的新能力。
Tight junctions between intestinal epithelial cells mediate the permeability of the intestinal barrier, and loss of intestinal barrier function mediated by TNF signaling is associated with the inflammatory pathophysiology observed in Crohn's disease and celiac disease. Thus, factors that modulate intestinal epithelial cell response to TNF may be critical for the maintenance of barrier function. TNF alpha-induced protein 3 (TNFAIP3) is a cytosolic protein that acts in a negative feedback loop to regulate cell signaling induced by Toll-like receptor ligands and TNF, suggesting that TNFAIP3 may play a role in regulating the intestinal barrier. To investigate the specific role of TNFAIP3 in intestinal barrier function we assessed barrier permeability in TNFAIP3−/− mice and LPS-treated villin-TNFAIP3 transgenic mice. TNFAIP3−/− mice had greater intestinal permeability compared to wild-type littermates, while villin-TNFAIP3 transgenic mice were protected from increases in permeability seen within LPS-treated wild-type littermates, indicating that barrier permeability is controlled by TNFAIP3. In cultured human intestinal epithelial cell lines, TNFAIP3 expression regulated both TNF-induced and myosin light chain kinase-regulated tight junction dynamics but did not affect myosin light chain kinase activity. Immunohistochemistry of mouse intestine revealed that TNFAIP3 expression inhibits LPS-induced loss of the tight junction protein occludin from the apical border of the intestinal epithelium. We also found that TNFAIP3 deubiquitinates polyubiquitinated occludin. These in vivo and in vitro studies support the role of TNFAIP3 in promoting intestinal epithelial barrier integrity and demonstrate its novel ability to maintain intestinal homeostasis through tight junction protein regulation.
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DOI：
10.4049/jimmunol.1000324
发表时间：
2010-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lodolce JP;Kolodziej LE;Rhee L;Kariuki SN;Franek BS;McGreal NM;Logsdon MF;Bartulis SJ;Perera MA;Ellis NA;Adams EJ;Hanauer SB;Jolly M;Niewold TB;Boone DL
通讯作者：
Boone DL
影响因子：
56.9
作者：
Lee, EG;Boone, DL;Ma, A
通讯作者：
Ma, A
6q23 上 TNFAIP3 附近的遗传变异与系统性红斑狼疮相关。
影响因子：
30.8
作者：
Graham, Robert R.;Cotsapas, Chris;Davies, Leela;Hackett, Rachel;Lessard, Christopher J.;Leon, Joanlise M.;Burtt, Noel P.;Guiducci, Candace;Parkin, Melissa;Gates, Casey;Plenge, Robert M.;Behrens, Timothy W.;Wither, Joan E.;Rioux, John D.;Fortin, Paul R.;Graham, Deborah Cunninghame;Wong, Andrew K.;Vyse, Timothy J.;Daly, Mark J.;Altshuler, David;Moser, Kathy L.;Gaffney, Patrick M.
通讯作者：
Gaffney, Patrick M.
影响因子：
24.5
作者：
Arrieta, M. C.;Madsen, K.;Doyle, J.;Meddings, J.
通讯作者：
Meddings, J.
影响因子：
3
作者：
Beutler, B;Kruys, V
通讯作者：
Kruys, V