Receptor interacting protein-2 plays a critical role in human lung epithelial cells survival in response to Fas-induced cell-death.
Receptor interacting protein-2 plays a critical role in human lung epithelial cells survival in response to Fas-induced cell-death.
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DOI：
10.1371/journal.pone.0092731
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wewers MD
中科院分区：
文献类型：
--
作者：
Rahman MA;Sundaram K;Mitra S;Gavrilin MA;Wewers MD
肺上皮细胞死亡是急性呼吸窘迫综合征肺损伤的关键。已知FasL在该肺细胞死亡途径中起重要作用，并且可能部分通过激活受体相互作用蛋白-2（RIP 2）起作用。RIP 2是具有C-末端半胱天冬酶激活和募集结构域（CARD）的丝氨酸/苏氨酸激酶。该CARD含有高度保守的预测酪氨酸磷酸化位点。因此，参与RIP 2的CARD结构域中的酪氨酸磷酸化可能在人肺免疫系统中Fas介导的细胞凋亡中起关键作用。为了检验这一假设，在操纵和不操纵内源性RIP 2浓度的情况下，诱导人肺上皮细胞（BEAS-2B）响应于Fas激动剂抗体CH 11而经历细胞死亡。我们表明，CH 11增加肺上皮细胞死亡的剂量依赖性的方式，确定LDH释放和核凝聚。Fas诱导的LDH释放被RIP 2敲低抑制。用RIP 2 siRNA处理后，BEAS-2B细胞中RIP 2水平的降低通过免疫印迹证实。RIP 2在BEAS-2B细胞中的过表达与Fas配体诱导的LDH释放呈剂量依赖性协同作用。最后，RIP 2的CARD中的酪氨酸磷酸化位点的突变保护BEAS-2B细胞免于Fas配体诱导的细胞死亡。因此，RIP 2的CARD酪氨酸磷酸化可能代表一个新的治疗靶点，以促进人类肺上皮细胞在导致急性肺损伤和ARDS的疾病中的存活。
Lung epithelial cell death is critical to the lung injury that occurs in the acute respiratory distress syndrome. It is known that FasL plays a prominent role in this lung cell death pathway and may work in part through activation of the receptor interacting protein-2 (RIP2). RIP2 is serine/threonine kinase with a C-terminal caspase activation and recruitment domain (CARD). This CARD contains a highly conserved, predicted tyrosine phosphorylation site. Thus, involvement of tyrosine phosphorylation in the CARD domain of RIP2 may play a critical role in Fas-mediated apoptosis in the human lung immune system. To test this hypothesis, human lung epithelial cells (BEAS-2B) were induced to undergo cell death in response to the Fas agonist antibody CH11 with and without manipulation of endogenous RIP2 concentrations. We show that CH11 increases lung epithelial cell death in a dose-dependent manner as determined by LDH release and nuclear condensation. Fas-induced LDH release was inhibited by RIP2 knock-down. Reduced levels of RIP2 in BEAS-2B cells after treatment with RIP2 siRNA were confirmed by immunoblot. Overexpression of RIP2 in BEAS-2B cells synergized with Fas ligand-induced LDH release in a dose-dependent manner. Finally, mutation of the tyrosine phosphorylation site in CARD of RIP2 protected BEAS-2B cells from Fas ligand induced cell death. Thus RIP2's CARD tyrosine phosphorylation may represent a new therapeutic target to promote the survival of human lung epithelial cells in disorders that lead to acute lung injury and ARDS.
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DOI：
10.1073/pnas.0504271103
发表时间：
2006-01-03
影响因子：
11.1
作者：
Gavrilin, MA;Bouakl, IJ;Wewers, MD
通讯作者：
Wewers, MD
DOI：
10.1164/rccm.200703-418oc
发表时间：
2008-05-01
影响因子：
24.7
作者：
Fahy, Ruairi J.;Exline, Matthew C.;Wewers, Mark D.
通讯作者：
Wewers, Mark D.
DOI：
10.1073/pnas.94.21.11333
发表时间：
1997-10-14
影响因子：
11.1
作者：
Han, DKM;Chaudhary, PM;Hood, L
通讯作者：
Hood, L
影响因子：
9.8
作者：
Lesage, S;Zouali, H;Hugot, JP
通讯作者：
Hugot, JP
影响因子：
5.6
作者：
Blom, N;Gammeltoft, S;Brunak, S
通讯作者：
Brunak, S