Ferran C, Stroka D M, Badrichani A Z, Cooper J T, Wrighton C J, Soares M, Grey S T, Bach F H
Department of Surgery, Center for Immunobiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA 02215, USA.
Blood. 1998 Apr 1;91(7):2249-58.
Expression of the NF-kappaB-dependent gene A20 in endothelial cells (EC) inhibits tumor necrosis factor (TNF)-mediated apoptosis in the presence of cycloheximide and acts upstream of IkappaBalpha degradation to block activation of NF-kappaB. Although inhibition of NF-kappaB by IkappaBalpha renders cells susceptible to TNF-induced apoptosis, we show that when A20 and IkappaBalpha are coexpressed, the effect of A20 predominates in that EC are rescued from TNF-mediated apoptosis. These findings place A20 in the category of "protective" genes that are induced in response to inflammatory stimuli to protect EC from unfettered activation and from undergoing apoptosis even when NF-kappaB is blocked. From a therapeutic perspective, genetic engineering of EC to express an NF-kappaB inhibitor such as A20 offers the mean of achieving an anti-inflammatory effect without sensitizing the cells to TNF-mediated apoptosis.
内皮细胞（EC）中核因子κB（NF-κB）依赖性基因A20的表达，在存在放线菌酮的情况下可抑制肿瘤坏死因子（TNF）介导的细胞凋亡，并且在IκBα降解的上游发挥作用以阻断NF-κB的激活。虽然IκBα对NF-κB的抑制使细胞易受TNF诱导的细胞凋亡影响，但我们发现，当A20和IκBα共表达时，A20的作用占主导，因为内皮细胞可从TNF介导的细胞凋亡中得到挽救。这些发现将A20归入“保护性”基因类别，这类基因在炎症刺激下被诱导表达，以保护内皮细胞免受不受控制的激活，即使在NF-κB被阻断时也能防止其发生凋亡。从治疗角度来看，通过基因工程使内皮细胞表达如A20这样的NF-κB抑制剂，提供了一种在不使细胞对TNF介导的细胞凋亡敏感的情况下实现抗炎作用的方法。
