TL1A both promotes and protects from renal inflammation and injury
TL1A both promotes and protects from renal inflammation and injury
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DOI：
10.1681/asn.2007060706
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发表时间：
2008-05-01
影响因子：
13.6
通讯作者：
Bradley, John R.
中科院分区：
文献类型：
--
作者：
Al-Lamki, Rafia S.;Wang, Jun;Bradley, John R.
死亡受体 3 (DR3) 是 TNF 受体 (TNFR) 超家族的成员，在人肾小管上皮细胞 (TEC) 中响应损伤而被诱导。本研究检测了 DR3 的主要配体 TL1A 的表达和作用。在肾同种异体移植物活检或肾切除标本的组织学正常组织中，TL1A mRNA 和蛋白在血管内皮细胞中表达，但在 TEC 中不表达。在急性或抗体介导的同种异体移植排斥的标本中，血管内皮细胞和浸润白细胞表达增加的TL1A mRNA和蛋白，但TEC表达TL1A蛋白而不表达mRNA，这与外源配体的摄取一致。将 TL1A 添加到人或小鼠肾脏的器官培养物中会导致 TEC 中 NF-kappa B 的激活、TNFR2 的表达、caspase-3 的激活和细胞凋亡。抑制 NF-κ B 激活会增加 TL1A 介导的 caspase-3 激活和 TEC 细胞凋亡，但不会减少 TNFR2 的诱导。在缺乏 DR3 的小鼠肾脏的器官培养中，添加 TL1A 会诱导 TNFR2，但不会激活 NF-κ B，也不会增加 TEC 的凋亡。这些数据表明，TL1A 可能通过 DR3 介导的 NF-kappa B 和 caspase-3 激活分别导致肾脏炎症和损伤，但未识别的受体可能介导 TEC 中 NF-kappa B 不依赖的 TNFR2 诱导。
Death receptor 3 (DR3), a member of the TNF receptor (TNFR) superfamily, is induced in human renal tubular epithelial cells (TEC) in response to injury. This study examined the expression and actions of TL1A, the principal ligand for DR3. In histologically normal tissue from biopsy or nephrectomy specimens of renal allografts, TL1A mRNA and protein were expressed in vascular endothelial cells but not in TEC. In specimens of acute or anti body-mediated allograft rejection, vascular endothelial cells and infiltrating leukocytes expressed increased TL1A mRNA and protein, but TEC expressed TL1A protein without mRNA, consistent with uptake of exogenous ligand. Addition of TL1A to organ cultures of human or mouse kidney caused activation of NF-kappa B, expression of TNFR2, activation of caspase-3, and apoptosis in TEC. Inhibition of NF-kappa B activation increased TL1A-mediated caspase-3 activation and apoptosis of TEC, but it did not reduce the induction of TNFR2. In organ culture of DR3-deficient mouse kidneys, addition of TL1A induced TNFR2 but did not activate NF-kappa B and did not increase apoptosis of TEC. These data suggest that TL1A may contribute to renal inflammation and injury through DR3-mediated activation of NF-kappa B and caspase-3, respectively, but that an unidentified receptor may mediate the NF-kappa B-independent induction of TNFR2 in TEC.