Intestinal Expression of Fas and Fas Ligand Is Upregulated by Bacterial Signaling through TLR4 and TLR5, with Activation of Fas Modulating Intestinal TLR-Mediated Inflammation
Intestinal Expression of Fas and Fas Ligand Is Upregulated by Bacterial Signaling through TLR4 and TLR5, with Activation of Fas Modulating Intestinal TLR-Mediated Inflammation
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DOI：
10.4049/jimmunol.1303083
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发表时间：
2014-12-15
影响因子：
4.4
通讯作者：
Houston, Aileen
中科院分区：
文献类型：
--
作者：
Fernandes, Philana;O'Donnell, Charlotte;Houston, Aileen
TLR 在介导肠道炎症和体内平衡中发挥着重要作用。 Fas 的最佳研究是其在细胞凋亡中的功能，但最近的研究表明 Fas 信号传导可能介导其他功能，例如炎症。 Fas 和 Fas 配体 (FasL) 在肠道中的作用尚不清楚。本研究的目的是评估肠上皮细胞 (IEC) 中 TLR 和 Fas/FasL 系统之间潜在的串扰。用 TLR 配体刺激 IEC，并研究 Fas 和 FasL 的表达。在体外，用 TLR4 和 TLR5 配体（而非 TLR2 和 9 配体）处理可增加 IEC 中 Fas 和 FasL 的表达。与这一发现一致的是，在 TLR4 敲除 (KO)、5KO 和无菌小鼠的上皮细胞中，肠道 Fas 和 FasL 的表达在体内降低，但在 TLR2KO 小鼠中则没有。使用激动性抗 Fas 调节 Fas 信号传导可增强 IEC 产生的 TLR4 和 TLR5 介导的 TNF-α 和 IL-8。此外，抑制IEC中的Fas会降低TLR4和TLR5配体以及肠道病原体鼠伤寒沙门氏菌和单核细胞增生李斯特氏菌诱导IL-8表达的能力。总之，本研究表明，IEC 中 Fas 和 TLR 信号通路之间存在广泛的串扰，FasL/Fas 系统在 TLR 介导的肠道炎症反应中发挥作用。
TLRs play an important role in mediating intestinal inflammation and homeostasis. Fas is best studied in terms of its function in apoptosis, but recent studies demonstrate that Fas signaling may mediate additional functions such as inflammation. The role of Fas, and the Fas ligand (FasL), in the intestine is poorly understood. The aim of this study was to evaluate potential cross-talk between TLRs and Fas/FasL system in intestinal epithelial cells (IECs). IECs were stimulated with TLR ligands, and expression of Fas and FasL was investigated. Treatment with TLR4 and TLR5 ligands, but not TLR2 and 9 ligands, increased expression of Fas and FasL in IECs in vitro. Consistent with this finding, expression of intestinal Fas and FasL was reduced in vivo in the epithelium of TLR4 knockout (KO), 5KO, and germ-free mice, but not in TLR2KO mice. Modulating Fas signaling using agonistic anti-Fas augmented TLR4- and TLR5-mediated TNF-alpha and IL-8 production by IECs. In addition, suppression of Fas in IECs reduced the ability of TLR4 and TLR5 ligands and the intestinal pathogens Salmonella typhimurium and Listeria monocytogenes to induce the expression of IL-8. In conclusion, this study demonstrates that extensive cross-talk in IECs occurs between the Fas and TLR signaling pathways, with the FasL/Fas system playing a role in TLR-mediated inflammatory responses in the intestine.