FLICE-like inhibitory protein (FLIP) protects against apoptosis and suppresses NF-K13 activation induced by bacterial lipopolysaccharide
FLICE-like inhibitory protein (FLIP) protects against apoptosis and suppresses NF-K13 activation induced by bacterial lipopolysaccharide
复制标题
DOI：
10.1016/s0002-9440(10)63400-1
复制
发表时间：
2004-10-01
影响因子：
6
通讯作者：
Harlan, JM
中科院分区：
文献类型：
--
作者：
Bannerman, DD;Eiting, KT;Harlan, JM
细菌脂多糖(LPS)通过激活Toll样受体-4，在革兰氏阴性脓毒症相关的血管损伤/功能障碍中起重要作用。抑制新基因表达可使内皮细胞对脂多糖诱导的细胞凋亡敏感，其发生与类FLICE抑制蛋白(FLEP)表达减少有关。我们现在有数据确凿地证实了FLEP在保护EC免受内毒素诱导的细胞凋亡中的作用。FliP的过表达可保护细胞免受内毒素诱导的细胞凋亡，而反义寡核苷酸则下调FliP的表达；使EC敏化以直接杀死内毒素。有趣的是，FLEP的过表达抑制了脂多糖诱导的NF-kappaB的激活，但不能抑制佛波酯的激活，这表明FLEP在介导内毒素激活中具有特定的作用。相反，从Flip-/-小鼠获得的小鼠胚胎成纤维细胞(MEF)比从野生型小鼠获得的小鼠胚胎成纤维细胞(MEF)显示出增强了内毒素诱导的NF-kappaB的活性。FliP-/-MEF与全长Flio的重组逆转了脂多糖诱导的Flip-/-细胞中NF-kappaB活性的增强。FLEP的表达变化对其他已知的内毒素/TIR-4激活的信号通路，包括p38、Akt和JNK通路没有明显的影响。综上所述，这些数据支持FLIP在介导内毒素诱导的细胞凋亡和核因子-kappaB激活中的双重作用。
Bacterial lipopolysaccharide (LPS) via its activation of Toll-like receptor-4 contributes to much of the vascular injury/dysfunction associated with gram-negative sepsis. Inhibition of de novo gene expression has been shown to sensitize endothelial cells (EC) to LPS-induced apoptosis, the onset of which correlates with decreased expression of FLICE-like inhibitory protein (FLEP). We now have data that conclusively establish a role for FLEP in protecting EC against LPS-induced apoptosis. Overexpression of FLIP protected against LPS-induced apoptosis, whereas down-regulation of FLIP using antisense oligonucleotides; sensitized EC to direct LPS killing. Interestingly, FLEP overexpression suppressed NF-kappaB activation induced by LPS, but not by phorbol ester, suggesting a specific role for FLIP in mediating LPS activation. Conversely, mouse embryo fibroblasts (MEF) obtained from FLIP -/- mice showed enhanced LPS-induced NF-kappaB activation relative to those obtained from wild-type mice. Reconstitution of FLIP-/- MEF with full-length FLIP reversed the enhanced NF-kappaB activity elicited by LPS in the FLIP -/- cells. Changes in the expression of FLEP had no demonstrable effect on other known LPS/Tir-4-activated signaling pathways including the p38, Akt, and Jnk pathways. Together, these data support a dual role for FLIP in mediating LPS-induced apoptosis and NF-kappaB activation.