Type I interferon drives tumor necrosis factor-induced lethal shock.
Type I interferon drives tumor necrosis factor-induced lethal shock.
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DOI：
10.1084/jem.20090213
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发表时间：
2009-08-31
期刊：
影响因子：
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通讯作者：
Libert C
中科院分区：
文献类型：
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作者：
Huys L;Van Hauwermeiren F;Dejager L;Dejonckheere E;Lienenklaus S;Weiss S;Leclercq G;Libert C
肿瘤坏死因子被认为具有很强的抗肿瘤作用，但它也是一种很强的促炎细胞因子。在人类和小鼠体内注射肿瘤坏死因子会导致全身性炎症反应综合征，主要影响肝脏和肠道。肿瘤坏死因子也是几种炎症性疾病的中心介质。我们报道，I型干扰素(IFN)是肿瘤坏死因子致死反应的重要介质。缺乏干扰素-α受体1(IFNAR-1)或干扰素-β的小鼠对肿瘤坏死因子诱导的低温和死亡具有显著的抵抗力。与野生型(WT)小鼠相比，注射肿瘤坏死因子后，IFNAR-1−/−小鼠产生的IL-6减少，肠道损伤减轻，肠细胞和肝细胞凋亡减少。WT和IFNAR-1−/−小鼠肝脏中广泛的基因表达分析表明，该基因敲除小鼠对肿瘤坏死因子的反应存在很大缺陷，尤其是干扰素刺激的反应元件依赖基因，其中许多基因编码趋化因子。免疫组织化学检测发现，−/−小鼠肝脏中有较少的白细胞(WBC)浸润。I型干扰素信号的缺失为在荷瘤小鼠中潜在更安全的治疗使用肿瘤坏死因子提供了足够的保护。我们的数据表明，I型干扰素在肿瘤坏死因子诱导的致死性炎症性休克中起重要的中介作用，可能是通过促进细胞死亡、诱导趋化因子和白细胞在组织中的渗透而实现的。
Tumor necrosis factor (TNF) is reputed to have very powerful antitumor effects, but it is also a strong proinflammatory cytokine. Injection of TNF in humans and mice leads to a systemic inflammatory response syndrome with major effects on liver and bowels. TNF is also a central mediator in several inflammatory diseases. We report that type I interferons (IFNs) are essential mediators of the lethal response to TNF. Mice deficient in the IFN-α receptor 1 (IFNAR-1) or in IFN-β are remarkably resistant to TNF-induced hypothermia and death. After TNF injection, IFNAR-1−/− mice produced less IL-6, had less bowel damage, and had less apoptosis of enterocytes and hepatocytes compared with wild-type (WT) mice. Extensive gene expression analysis in livers of WT and IFNAR-1−/− mice revealed a large deficiency in the response to TNF in the knockout mice, especially of IFN-stimulated response element–dependent genes, many of which encode chemokines. In livers of IFNAR-1−/− mice, fewer infiltrating white blood cells (WBCs) were detected by immunohistochemistry. Deficiency of type I IFN signaling provided sufficient protection for potentially safer therapeutic use of TNF in tumor-bearing mice. Our data illustrate that type I IFNs act as essential mediators in TNF-induced lethal inflammatory shock, possibly by enhancing cell death and inducing chemokines and WBC infiltration in tissues.