IκB-kinase/nuclear factor-κB signaling prevents thermal injury-induced gut damage by inhibiting c-Jun NH2-terminal kinase activation
IκB-kinase/nuclear factor-κB signaling prevents thermal injury-induced gut damage by inhibiting c-Jun NH2-terminal kinase activation
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DOI：
10.1097/01.ccm.0000261891.30360.f0
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发表时间：
2007-05-01
影响因子：
8.8
通讯作者：
Hsu, Ching-Mei
中科院分区：
文献类型：
--
作者：
Chen, Lee-Wei;Chen, Pei-Hsuan;Hsu, Ching-Mei
目的：严重烧伤后肠道损伤的分子机制尚不清楚。本研究旨在确定肠粘膜中的IKB-激酶（IKK）/核因子-KB信号传导是否通过调节c-Jun NH 2-末端激酶（JNK）和p38磷酸化来维持肠道功能。设计：前瞻性实验研究。设置：大学医院的研究实验室。受试者：小鼠热损伤模型。干预措施：条件性肠上皮细胞IKK β敲除（Vil-Cre/Ikk β（F/Delta））小鼠和对照（Ikk β（F/Delta））小鼠经受30%总体表面积的三度烧伤。JNK抑制剂（SP 600125）或p38抑制剂（SB 203580）在烧伤后立即给予小鼠。热损伤诱导肠通透性、核因子-KB DNA结合活性、磷酸化JNK磷酸化p38，Vil-Cre/Ikk β（F/Delta）小鼠肠粘膜caspase 3表达与Ikk β（F/Delta）小鼠比较。与Ikk β（F/Delta）小鼠相比，Vil-Cre/Ikk β（F/Delta）小鼠中BCL-xL和细胞FLICE抑制蛋白的mRNA表达显著降低，但GADD 45 β（生长停滞和DNA损伤诱导蛋白β）、细胞凋亡抑制因子1、BfI-1或TRAIL的mRNA表达不显著降低。SP 600125降低了Vil-Cre/Ikk β（F/Delta）小鼠肠通透性，并增加了肠粘膜磷酸化p38和肿瘤坏死因子受体相关因子2的表达。SB 203580治疗增强了Vil-Cre/Ikk beta（F/Delta）小鼠中热损伤诱导的肠道损伤。结论：热损伤诱导肠粘膜核因子-KB活化，IKK保护肠粘膜免受热损伤诱导的肠道损伤。IKK通过上调BCL-xL和细胞FLICE抑制蛋白表达来阻断caspase 3表达。IKK抑制JNK和p38的磷酸化，但不抑制p44/42的磷酸化。JNK抑制增加p38和肿瘤坏死因子受体相关因子2的表达并减少热损伤诱导的肠道损伤结合p38抑制增强热损伤诱导的肠道损伤，我们得出结论，IKK通过抑制JNK磷酸化来维持肠道功能，JNK磷酸化抑制p38磷酸化并诱导肠道损伤。
Objective: The molecular mechanism of major burn-induced gut damage is not clear. This study is to determine whether IKB-kinase (IKK)/nuclear factor-KB signaling in intestinal mucosa maintains gut function through the regulation of the c-Jun NH2- terminal kinase (JNK) and p38 phosphorylation.Design: Prospective, experimental study.Setting: Research laboratory at a university hospital.Subjects: Thermal injury models in mice.Interventions: Conditional intestinal epithelial cell IKK beta knockout (Vil-Cre/Ikk beta(F/Delta)) mice and control (Ikk beta(F/Delta)) mice were sub-jected to 30% total body surface area third-degree burn. JNK inhibitor (SP600125) or p38 inhibitor (SB203580) was given to mice immediately after burn injury.Measurements and Main Results: Thermal injury induced a significant increase of intestinal permeability, nuclear factor-KB DNA-binding activity, phosphorylated JNK phosphorylated p38, and caspase 3 expression of intestinal mucosa in Vil-Cre/Ikk beta(F/Delta) mice compared with those of Ikk beta(F/Delta) mice. BCL-xL and cellular FLICE inhibitory protein, but not GADD45 beta (growth arrest and DNA damage-inducing protein beta), cellular inhibitor of apoptosis 1, BfI-1, or TRAIL, messenger RNA expression was significantly decreased in Vil-Cre/Ikk beta(F/Delta) mice compared with that of Ikk beta(F/Delta) mice. SP600125 decreased intestinal permeability and increased phosphorylated p38 and tumor necrosis factor receptor-associated factor 2 expression of intestinal mucosa in Vil-Cre/Ikk beta(F/Delta) mice. SB203580 treatment enhanced thermal injury-induced gut damage in Vil-Cre/Ikk beta(F/Delta) mice.Conclusions: Thermal injury induces nuclear factor-KB activation of intestinal mucosa and IKK protects intestinal mucosa from thermal injury-induced gut damage. IKK blocks caspase 3 expression by up-regulating BCL-xL and cellular FLICE inhibitory protein expression. IKK inhibits JNK and p38 but not p44/42 phosphorylation of intestinal mucosa. JNK inhibition increases p38 and tumor necrosis factor receptor-associated factor 2 expression and decreases thermal injury-induced gut damage. Taken together with the enhanced thermal injury-induced gut damage by p38 inhibition, we conclude that IKK maintains gut function by inhibiting JNK phosphorylation, which suppresses p38 phosphorylation and induces gut damage.