STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines.
STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines.
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DOI：
10.4049/jimmunol.1201373
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发表时间：
2013-02-15
期刊：
影响因子：
--
通讯作者：
Wilson KT
中科院分区：
文献类型：
--
作者：
Rosen MJ;Chaturvedi R;Washington MK;Kuhnhein LA;Moore PD;Coggeshall SS;McDonough EM;Weitkamp JH;Singh AB;Coburn LA;Williams CS;Yan F;Van Kaer L;Peebles RS Jr;Wilson KT
患有溃疡性结肠炎（UC）的患者表现出由失调的粘膜免疫应答和上皮屏障破坏引起的慢性结肠炎症。包括IL-13在内的Th 2细胞因子与UC的发病机制有关。IL-13诱导STAT 6的磷酸化，我们先前已经证明UC儿童中上皮磷酸化（p）STAT 6增加。在这里，我们研究了STAT 6在恶唑酮结肠炎中的作用，这是一种UC小鼠模型，通过在STAT 6缺陷（STAT 6 −/−）和野生型（WT）小鼠中诱导结肠炎。我们在结肠炎WT小鼠中观察到上皮细胞、T细胞、巨噬细胞和NKT细胞STAT 6磷酸化增加，以及产生pSTAT 6 + IL-13的NKT细胞增加。结肠炎在STAT 6 −/−小鼠中减弱，体重、结肠长度和组织病理学改善。在STAT 6 −/−小鼠中，孔形成紧密连接蛋白claudin-2的诱导减少。类似地，在IL-13处理的人T84细胞中，shRNA STAT 6敲低降低了claudin-2诱导和跨上皮阻力降低。在WT和STAT 6 −/−结肠炎小鼠中，IL-13、IFN-γ、IL-17和IL-10 mRNA的组织表达被类似地诱导;然而，我们观察到在患有结肠炎的WT小鼠中，Th 2诱导细胞因子IL-33和胸腺基质淋巴细胞生成素（TSLP）的mRNA表达增加，而在STAT 6 −/−小鼠中则被消除。来自患有结肠炎的STAT 6 −/−小鼠的肠系膜淋巴结（MLN）细胞表现出IL-4、IL-5、IL-13和IFN-γ的分泌减少。IL-33增强了IL-5、IL-13、IL-6和IFN-γ的MLN细胞分泌。这些数据表明，STAT 6在结肠炎的发病机制中具有重要作用，在改变上皮屏障功能和调节Th 2诱导的细胞因子的产生。
Patients suffering from ulcerative colitis (UC) exhibit chronic colonic inflammation caused by a dysregulated mucosal immune response and epithelial barrier disruption. Th2 cytokines, including IL-13, have been implicated in the pathogenesis of UC. IL-13 induces phosphorylation of STAT6, and we have previously demonstrated increased epithelial phosphorylated (p)STAT6 in children with UC. Here, we investigated the role of STAT6 in oxazolone colitis, a murine model of UC, by inducing colitis in STAT6-deficient (STAT6−/−) and wild type (WT) mice. We observed increased epithelial cell, T cell, macrophage, and NKT cell STAT6 phosphorylation, and increased pSTAT6+ IL-13-producing NKT cells, in colitic WT mice. Colitis was attenuated in STAT6−/− mice with improvements in weight, colon length, and histopathology. There was decreased induction of the pore-forming tight junction protein claudin-2 in STAT6−/− mice. Similarly, shRNA STAT6 knockdown reduced claudin-2 induction and transepithelial resistance decrease in IL-13-treated human T84 cells. Tissue expression of IL-13, IFN-γ, IL-17, and IL-10 mRNA was similarly induced in WT and STAT6−/− colitic mice; however, we observed increased mRNA expression for the Th2-inducing cytokines IL-33 and thymic stromal lymphopoietin (TSLP) in WT mice with colitis, which was abrogated in STAT6−/− mice. Mesenteric lymph node (MLN) cells from STAT6−/− mice with colitis exhibited reduced secretion of IL-4, IL-5, IL-13, and IFN-γ. IL-33 augmented MLN cell secretion of IL-5, IL-13, IL-6, and IFN-γ. These data implicate STAT6 in the pathogenesis of colitis in vivo with important roles in altering epithelial barrier function and regulating Th2-inducing cytokine production.
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影响因子：
24.5
作者：
Iliev, I. D.;Spadoni, I.;Rescigno, M.
通讯作者：
Rescigno, M.
影响因子：
6
作者：
Okuda, Y;Takahashi, I;Kiyono, H
通讯作者：
Kiyono, H
影响因子：
64.8
作者：
Khor, Bernard;Gardet, Agnes;Xavier, Ramnik J.
通讯作者：
Xavier, Ramnik J.
DOI：
10.1084/jem.20030437
发表时间：
2004-02-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Iijima H;Neurath MF;Nagaishi T;Glickman JN;Nieuwenhuis EE;Nakajima A;Chen D;Fuss IJ;Utku N;Lewicki DN;Becker C;Gallagher TM;Holmes KV;Blumberg RS
通讯作者：
Blumberg RS
影响因子：
32.4
作者：
Kaplan, MH;Schindler, U;Grusby, MJ
通讯作者：
Grusby, MJ