c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis.
c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis.
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DOI：
10.1126/scisignal.2003558
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发表时间：
2012-12-18
影响因子：
7.3
通讯作者：
Nakano H
中科院分区：
文献类型：
--
作者：
Piao X;Komazawa-Sakon S;Nishina T;Koike M;Piao JH;Ehlken H;Kurihara H;Hara M;Van Rooijen N;Schütz G;Ohmuraya M;Uchiyama Y;Yagita H;Okumura K;He YW;Nakano H
作为半胱天冬酶-8的无催化活性同系物，c-FLIP通过结合并抑制半胱天冬酶-8来阻断凋亡。转录因子核因子κB（NF-κB）通过防止死亡受体诱导的细胞凋亡在维持肠和肝的稳态中起关键作用，并且c-FLIP在NF-κ B依赖性保护细胞免受死亡受体信号传导中起作用。由于c-Flip缺陷小鼠在子宫内死亡，我们产生了条件性c-Flip缺陷小鼠，以研究c-FLIP在发育和出生后阶段对肠道和肝脏稳态的贡献。肠上皮细胞（IEC）或肝细胞特异性缺失的c-Flip导致围产期死亡的结果增强的细胞凋亡和程序性坏死的IEC和肝细胞。编码肿瘤坏死因子-α（TNF-α）受体1（Tnfr 1）的基因缺陷部分挽救了IEC特异性c-Flip缺陷小鼠的围产期死亡率和结肠炎的发生，但不能挽救肝细胞特异性c-Flip缺陷小鼠的围产期死亡率。此外，c-Flip中干扰素（IFN）诱导缺陷的成年小鼠在c-FLIP耗尽后不久死于肝炎。用抗TNF-α、Fas配体（FasL）和TNF相关凋亡诱导配体（TRAIL）的中和抗体混合物预处理IFN诱导型c-Flip缺陷小鼠可预防肝炎。总之，这些结果表明，c-FLIP通过防止TNF-α、FasL和TRAIL诱导的细胞死亡来控制IEC和肝细胞的稳态。
As a catalytically inactive homolog of caspase-8, a proapoptotic initiator caspase, c-FLIP blocks apoptosis by binding to and inhibiting caspase-8. The transcription factor nuclear factor κB (NF-κB) plays a pivotal role in maintaining the homeostasis of the intestine and the liver by preventing death receptor–induced apoptosis, and c-FLIP plays a role in the NF-κB–dependent protection of cells from death receptor signaling. Because c-Flip–deficient mice die in utero, we generated conditional c-Flip–deficient mice to investigate the contribution of c-FLIP to homeostasis of the intestine and the liver at developmental and postnatal stages. Intestinal epithelial cell (IEC)– or hepatocyte-specific deletion of c-Flip resulted in perinatal lethality as a result of the enhanced apoptosis and programmed necrosis of the IECs and the hepatocytes. Deficiency in the gene encoding tumor necrosis factor–α (TNF-α) receptor 1 (Tnfr1) partially rescued perinatal lethality and the development of colitis in IEC-specific c-Flip–deficient mice but did not rescue perinatal lethality in hepatocyte-specific c-Flip–deficient mice. Moreover, adult mice with interferon (IFN)– inducible deficiency in c-Flip died from hepatitis soon after depletion of c-FLIP. Pretreatment of IFN-inducible c-Flip–deficient mice with a mixture of neutralizing antibodies against TNF-α, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL) prevented hepatitis. Together, these results suggest that c-FLIP controls the homeostasis of IECs and hepatocytes by preventing cell death induced by TNF-α, FasL, and TRAIL.
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DOI：
10.1084/jem.20082152
发表时间：
2009-08-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Beraza N;Malato Y;Sander LE;Al-Masaoudi M;Freimuth J;Riethmacher D;Gores GJ;Roskams T;Liedtke C;Trautwein C
通讯作者：
Trautwein C
影响因子：
8.8
作者：
Dillon CP;Oberst A;Weinlich R;Janke LJ;Kang TB;Ben-Moshe T;Mak TW;Wallach D;Green DR
通讯作者：
Green DR
影响因子：
50.3
作者：
Luedde, Tom;Beraza, Naiara;Pasparakis, Manolis
通讯作者：
Pasparakis, Manolis
影响因子：
64.5
作者：
Cho YS;Challa S;Moquin D;Genga R;Ray TD;Guildford M;Chan FK
通讯作者：
Chan FK
影响因子：
14.8
作者：
Degterev, Alexei;Hitomi, Junichi;Yuan, Junying
通讯作者：
Yuan, Junying