TPN-associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways
TPN-associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways
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DOI：
10.1096/fj.14-269480
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发表时间：
2015-07-01
期刊：
影响因子：
4.8
通讯作者：
Teitelbaum, Daniel H.
中科院分区：
文献类型：
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作者：
Freeman, Jennifer J.;Feng, Yongjia;Teitelbaum, Daniel H.
最近的研究表明，表皮生长因子（EGF）和TLR信号在肠上皮细胞（IEC）增殖的调制之间的密切相互作用;然而，这些信号通路如何调节IEC增殖知之甚少。我们利用全肠外营养（TPN）或肠内营养剥夺模型来研究这种相互作用，因为TPN导致粘膜萎缩，这是由于IEC增殖减少和凋亡增加。我们发现了新的发现，即接受TPN的TLR4敲除（TLR4KO）小鼠的粘膜萎缩减少。我们假设EGF信号在TLR4KO-TPN小鼠中得以保留并防止粘膜萎缩。向C57 B1/6和品系匹配的TLR4 KO小鼠提供肠内喂养或TPN。检测IEC增殖和凋亡。在两组中检测细胞因子和生长因子丰度。为了检查这些途径的相互依赖性，使用了ErbB1药理学阻断。TPN几乎阻止了TLR4KO小鼠IEC增殖的显著下降，并且部分保留了肠长度。与野生型（WT）TPN小鼠相比，TLR 4KO-TPN小鼠的EGF显著增加，TNF-α降低。WT-TPN小鼠中的凋亡阳性隐窝细胞比TLR4KO-TPN小鼠高15倍。Bcl-2在TLR4KO-TPN小鼠中显著增加，而Bax降低10倍。ErbB1阻断阻止了TLR4KO-sTPN小鼠的这种保护作用。TLR4阻断通过保护增殖和防止凋亡显著防止TPN相关萎缩。这是由TNF-α丰度减少和EGF增加驱动的。对这一调节途径的潜在操纵可能具有预防TPN相关萎缩的显著临床潜力。
Recent studies suggest a close interaction between epidermal growth factor (EGF) and TLR signaling in the modulation of intestinal epithelial cell (IEC) proliferation; however, how these signaling pathways adjust IEC proliferation is poorly understood. We utilized a model of total parenteral nutrition (TPN), or enteral nutrient deprivation, to study this interaction as TPN results in mucosal atrophy due to decreased IEC proliferation and increased apoptosis. We identified the novel finding of decreased mucosal atrophy in TLR4 knockout (TLR4KO) mice receiving TPN. We hypothesized that EGF signaling is preserved in TLR4KO-TPN mice and prevents mucosal atrophy. C57Bl/6 and strain-matched TLR4KO mice were provided either enteral feeding or TPN. IEC proliferation and apoptosis were measured. Cytokine and growth factor abundances were detected in both groups. To examine interdependence of these pathways, ErbB1 pharmacologic blockade was used. The marked decline in IEC proliferation with TPN was nearly prevented in TLR4KO mice, and intestinal length was partially preserved. EGF was significantly increased, and TNF-alpha decreased in TLR4KO-TPN versus wild-type (WT)TPN mice. Apoptotic positive crypt cells were 15-fold higher in WT-TPN versus TLR4KO-TPN mice. Bcl-2 was significantly increased in TLR4KO-TPN mice, while Bax decreased 10-fold. ErbB1 blockade prevented this otherwise protective effect in TLR4KO-sTPN mice. TLR4 blockade significantly prevented TPN-associated atrophy by preserving proliferation and preventing apoptosis. This is driven by a reduction in TNF-alpha abundance and increased EGF. Potential manipulation of this regulatory pathway may have significant clinical potential to prevent TPN-associated atrophy.