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首页> 外文期刊>Molecular and Cellular Biology >Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition
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Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

机译：肠细胞中ADAM17介导的肿瘤坏死因子α信号的丢失减弱肠外营养小鼠模型的粘膜萎缩。

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Total parenteral nutrition (TPN) is commonly used clinically to sustain patients; however, TPN is associated with profound mucosal atrophy, which may adversely affect clinical outcomes. Using a mouse TPN model, removing enteral nutrition leads to decreased crypt proliferation, increased intestinal epithelial cell (IEC) apoptosis and increased mucosal tumor necrosis factor alpha (TNF-α) expression that ultimately produces mucosal atrophy. Upregulation of TNF-α signaling plays a central role in mediating TPN-induced mucosal atrophy without intact epidermal growth factor receptor (EGFR) signaling. Currently, the mechanism and the tissue-specific contributions of TNF-α signaling to TPN-induced mucosal atrophy remain unclear. ADAM17 is an ectodomain sheddase that can modulate the signaling activity of several cytokine/growth factor receptor families, including the TNF-α/TNF receptor and ErbB ligand/EGFR pathways. Using TPN-treated IEC-specific ADAM17-deficient mice, the present study demonstrates that a loss of soluble TNF-α signaling from IECs attenuates TPN-induced mucosal atrophy. Importantly, this response remains dependent on the maintenance of functional EGFR signaling in IECs. TNF-α blockade in wild-type mice receiving TPN confirmed that soluble TNF-α signaling is responsible for downregulation of EGFR signaling in IECs. These results demonstrate that ADAM17-mediated TNF-α signaling from IECs has a significant role in the development of the proinflammatory state and mucosal atrophy observed in TPN-treated mice.
机译：全肠外营养（TPN）在临床上通常用于维持患者的生命。然而，TPN与严重的粘膜萎缩有关，可能会对临床结果产生不利影响。使用小鼠TPN模型，去除肠内营养会导致隐窝增殖减少，肠上皮细胞（IEC）凋亡增加以及粘膜肿瘤坏死因子α（TNF-α）表达增加，最终导致粘膜萎缩。 TNF-α信号的上调在没有完整表皮生长因子受体（EGFR）信号的情况下介导TPN诱导的粘膜萎缩中起着核心作用。目前，尚不清楚TNF-α信号转导TPN诱导的粘膜萎缩的机制和组织特异性贡献。 ADAM17是一种胞外域脱氢酶，可以调节几个细胞因子/生长因子受体家族的信号传导活性，包括TNF-α/ TNF受体和ErbB配体/ EGFR途径。使用TPN治疗的IEC特异性ADAM17缺陷型小鼠，本研究表明IEC产生的可溶性TNF-α信号丢失可减弱TPN诱导的粘膜萎缩。重要的是，这种反应仍然取决于IEC中功能性EGFR信号传导的维持。接受TPN的野生型小鼠中的TNF-α阻断证实，可溶性TNF-α信号传导可导致IECs中EGFR信号的下调。这些结果表明，IECs的ADAM17介导的TNF-α信号传导在TPN处理的小鼠的促炎状态和粘膜萎缩的发生中具有重要作用。

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