Protection of epithelial barrier function by the Crohn's disease associated gene protein tyrosine phosphatase n2.
Protection of epithelial barrier function by the Crohn's disease associated gene protein tyrosine phosphatase n2.
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DOI：
10.1053/j.gastro.2009.07.078
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发表时间：
2009-12
期刊：
影响因子：
29.4
通讯作者：
McCole DF
中科院分区：
文献类型：
--
作者：
Scharl M;Paul G;Weber A;Jung BC;Docherty MJ;Hausmann M;Rogler G;Barrett KE;McCole DF
蛋白酪氨酸磷酸酶N2（PTPN2）已被确定为克罗恩病（CD）的候选基因。然而，PTPN2在CD发病机制中的作用尚未明确。肠道上皮通透性增加被认为在CD中起重要作用。本研究的目的是确定PTPN2在CD发病机制中可能的作用。
所有研究均使用肠道上皮细胞（IEC）系T84和HT29cl.19a。通过蛋白质印迹法进行蛋白质分析，通过小干扰RNA（siRNA）诱导蛋白质敲低。原代样本来自对照组和CD患者。
在此，我们证明在CD肠道活检组织中PTPN2表达增加，并且促炎细胞因子干扰素γ（IFNγ）增加IEC中PTPN2的表达和活性。此外，PTPN2敲低增强了IEC中IFNγ诱导的信号转导及转录激活因子1（STAT1）和STAT3的磷酸化。细胞能量传感器腺苷酸活化蛋白激酶（AMPK）部分调节IFNγ对PTPN2的诱导作用。此外，PTPN2敲低增强了IFNγ诱导的上皮通透性增加，并伴有成孔蛋白克劳丁 - 2（claudin - 2）表达升高。
PTPN2被IFNγ激活，并限制IFNγ诱导的信号传导以及随之而来的屏障缺陷。这些数据表明PTPN2在维持肠道上皮屏障以及CD病理生理学方面具有功能性作用。
Protein tyrosine phosphatase N2 (PTPN2) has been identified as a Crohn’s disease (CD) candidate gene. However, a role for PTPN2 in the pathogenesis of CD has not been identified. Increased permeability of the intestinal epithelium is believed to contribute prominently to CD. The aim of this study was to determine a possible role for PTPN2 in CD pathogenesis. Intestinal epithelial cell (IEC) lines, T84 and HT29cl.19a, were used in all studies. Protein analysis was performed by Western blotting and protein knock-down was induced by siRNA. Primary samples were from control and CD patients. Here, we demonstrate increased PTPN2 expression in CD intestinal biopsies and that the pro-inflammatory cytokine, IFNγ, increases PTPN2 expression and activity in IEC. Moreover, IFNγ-induced STAT1 and STAT3 phosphorylation in IEC is enhanced by PTPN2 knock-down. The cellular energy sensor, AMPK, partially regulates the IFNγ-induced effects on PTPN2. Additionally, PTPN2 knock-down potentiates IFNγ-induced increases in epithelial permeability, accompanied by elevated expression of the pore-forming protein, claudin-2. PTPN2 is activated by IFNγ and limits IFNγ-induced signalling and consequent barrier defects. These data suggest a functional role for PTPN2 in maintaining the intestinal epithelial barrier and in the pathophysiology of CD.
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影响因子：
30.8
作者：
Fisher, Sheila A.;Tremelling, Mark;Anderson, Carl A.;Gwilliam, Rhian;Bumpstead, Suzannah;Prescott, Natalie J.;Nimmo, Elaine R.;Massey, Dunecan;Berzuini, Carlo;Johnson, Christopher;Barrett, Jeffrey C.;Cummings, Fraser R.;Drummond, Hazel;Lees, Charlie W.;Onnie, Clive M.;Hanson, Catherine E.;Blaszczyk, Katarzyna;Inouye, Mike;Ewels, Philip;Ravindrarajah, Radhi;Keniry, Andrew;Hunt, Sarah;Carter, Martyn;Watkins, Nick;Ouwehand, Willem;Lewis, Cathryn M.;Cardon, Lon;Lobo, Alan;Forbes, Alastair;Sanderson, Jeremy;Jewell, Derek P.;Mansfield, John C.;Deloukas, Panos;Mathew, Christopher G.;Parkes, Miles;Satsangi, Jack
通讯作者：
Satsangi, Jack
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
15.9
作者：
MADARA, JL;STAFFORD, J
通讯作者：
STAFFORD, J
影响因子：
29.4
作者：
Schmitz, H;Barmeyer, C;Schulzke, JD
通讯作者：
Schulzke, JD
影响因子：
5.3
作者：
Galic, S;Klingler-Hoffmann, M;Tiganis, T
通讯作者：
Tiganis, T