Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice.
Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice.
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DOI：
10.1002/hep.23510
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发表时间：
2010-05
期刊：
影响因子：
13.5
通讯作者：
Robson, Simon C.
中科院分区：
文献类型：
--
作者：
Beldi, Guido;Banz, Yara;Kroemer, Alexander;Sun, Xiaofeng;Wu, Yan;Graubardt, Nadine;Rellstab, Alyssa;Nowak, Martina;Enjyoji, Keiichi;Li, Xian;Junger, Wolfgang G.;Candinas, Daniel;Robson, Simon C.
自然杀伤（NK）细胞在先天免疫中起着至关重要的作用，并表达CD 39（外核苷酸三磷酸二磷酸水解酶1 [E-NTPD 1]），这是一种将细胞外核苷酸磷酸水解为腺苷的限速外核苷酸酶。我们研究了部分肝缺血/再灌注损伤（IRI）后CD 39基因缺失对NK细胞的影响。我们在小鼠中发现，CD 39基因缺失与NK细胞上三磷酸腺苷（ATP）和二磷酸腺苷磷酸化为一磷酸腺苷的磷酸水解显著减少有关，从而调节这些细胞上显示的2型嘌呤能（P2）受体。我们注意到，CD 39-null小鼠受到保护，免受急性血管损伤后，单叶温暖的IRI，并相对于对照野生型小鼠，显示出显着较少的升高转氨酶与不太明显的组织病理学变化与IRI。将免疫细胞选择性过继转移到Rag 2/普通γ缺陷小鼠（T细胞、B细胞和NK/NKT细胞缺陷）中表明，是NK细胞上的CD 39缺失提供了终末器官保护，这与在不存在干扰素γ的情况下观察到的相当。事实上，NK效应机制如干扰素γ分泌在体外被P2受体活化抑制。具体而言，ATPγS（一种不可水解的ATP类似物）抑制NK细胞响应白细胞介素-12和白细胞介素-18分泌干扰素γ，在CD 39缺失和细胞因子分泌改变之间提供了机制联系。我们认为，CD 39缺陷和P2受体活化的变化消除了NK细胞对炎症介质的干扰素γ分泌，从而限制了IRI期间这些先天免疫细胞介导的组织损伤。
Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ectonucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after partial hepatic ischemia/reperfusion injury (IRI). We show in mice that gene deletion of CD39 is associated with marked decreases in phosphohydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate on NK cells, thereby modulating the type-2 purinergic (P2) receptors demonstrated on these cells. We note that CD39-null mice are protected from acute vascular injury after single-lobe warm IRI, and, relative to control wild-type mice, display significantly less elevation of aminotransferases with less pronounced histopathological changes associated with IRI. Selective adoptive transfers of immune cells into Rag2/common gamma null mice (deficient in T cells, B cells, and NK/NKT cells) suggest that it is CD39 deletion on NK cells that provides end-organ protection, which is comparable to that seen in the absence of interferon gamma. Indeed, NK effector mechanisms such as interferon gamma secretion are inhibited by P2 receptor activation in vitro. Specifically, ATPγS (a nonhydrolyzable ATP analog) inhibits secretion of interferon gamma by NK cells in response to interleukin-12 and interleukin-18, providing a mechanistic link between CD39 deletion and altered cytokine secretion. We propose that CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, thereby limiting tissue damage mediated by these innate immune cells during IRI.
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DOI：
10.1084/jem.20061097
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lappas CM;Day YJ;Marshall MA;Engelhard VH;Linden J
通讯作者：
Linden J
影响因子：
8.8
作者：
Osborne, FN;Kalsi, KK;Smolenski, RT
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影响因子：
13.5
作者：
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Miyazaki, M
影响因子：
20.3
作者：
Sévigny, J;Sundberg, C;Robson, SC
通讯作者：
Robson, SC
影响因子：
7.7
作者：
Friedman, David J.;Rennke, Helmut G.;Robson, Simon C.
通讯作者：
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