Platelet-activating factor induces TLR4 expression in intestinal epithelial cells: implication for the pathogenesis of necrotizing enterocolitis.
Platelet-activating factor induces TLR4 expression in intestinal epithelial cells: implication for the pathogenesis of necrotizing enterocolitis.
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DOI：
10.1371/journal.pone.0015044
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发表时间：
2010-10-15
期刊：
影响因子：
3.7
通讯作者：
Jilling T
中科院分区：
文献类型：
--
作者：
Soliman A;Michelsen KS;Karahashi H;Lu J;Meng FJ;Qu X;Crother TR;Rabizadeh S;Chen S;Caplan MS;Arditi M;Jilling T
坏死性小肠结肠炎（NEC）是新生儿重症监护病房发病和死亡的主要原因，但其发病机制尚不完全清楚。我们以前已经表明，血小板活化因子（PAF），细菌和TLR 4都是NEC的发展中的重要因素。鉴于Toll样受体（TLR）在成熟胃肠道的肠上皮细胞中以低水平表达，但在实验性NEC中显示在肠上皮细胞中异常过度表达，我们使用人和小鼠体外细胞系以及离体大鼠肠袢模型研究了PAF对TLR 4表达和信号传导的调节。在肠上皮细胞（IEC）系中，PAF刺激产生TLR 4 mRNA和蛋白质表达的上调，并导致LPS刺激后IL-8分泌增加（在另外的LPS最低响应细胞系中）。PAF刺激导致人TLR 4启动子激活以剂量依赖性方式增加。Western blotting和免疫组化结果显示PAF可诱导IEC中STAT 3磷酸化和核转位，而PAF诱导的TLR 4表达可被STAT 3和NFκB抑制剂抑制。我们的研究结果为PAF通过异常TLR 4上调增强肠上皮炎症，从而促进NEC肠损伤的机制提供了证据。
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in neonatal intensive care units, however its pathogenesis is not completely understood. We have previously shown that platelet activating factor (PAF), bacteria and TLR4 are all important factors in the development of NEC. Given that Toll-like receptors (TLRs) are expressed at low levels in enterocytes of the mature gastrointestinal tract, but were shown to be aberrantly over-expressed in enterocytes in experimental NEC, we examined the regulation of TLR4 expression and signaling by PAF in intestinal epithelial cells using human and mouse in vitro cell lines, and the ex vivo rat intestinal loop model. In intestinal epithelial cell (IEC) lines, PAF stimulation yielded upregulation of both TLR4 mRNA and protein expression and led to increased IL-8 secretion following stimulation with LPS (in an otherwise LPS minimally responsive cell line). PAF stimulation resulted in increased human TLR4 promoter activation in a dose dependent manner. Western blotting and immunohistochemical analysis showed PAF induced STAT3 phosphorylation and nuclear translocation in IEC, and PAF-induced TLR4 expression was inhibited by STAT3 and NFκB Inhibitors. Our findings provide evidence for a mechanism by which PAF augments inflammation in the intestinal epithelium through abnormal TLR4 upregulation, thereby contributing to the intestinal injury of NEC.
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DOI：
10.1152/ajpgi.00328.2004
发表时间：
2005-05-01
影响因子：
4.5
作者：
Fukata, M;Michelsen, KS;Abreu, MT
通讯作者：
Abreu, MT
影响因子：
3.1
作者：
Cario, E;Podolsky, DK
通讯作者：
Podolsky, DK
影响因子：
3.6
作者：
Jilling, T;Lu, J;Caplan, MS
通讯作者：
Caplan, MS
影响因子：
4.8
作者：
HSUEH, W;GONZALEZCRUSSI, F;ARROYAVE, JL
通讯作者：
ARROYAVE, JL
DOI：
10.1007/s10024-002-0602-z
发表时间：
2003-01
期刊：
Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society
影响因子：
--
作者：
Hsueh W;Caplan MS;Qu XW;Tan XD;De Plaen IG;Gonzalez-Crussi F
通讯作者：
Gonzalez-Crussi F