Toll-like receptor 4 suppression leads to islet allograft survival
Toll-like receptor 4 suppression leads to islet allograft survival
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DOI：
10.1096/fj.06-7910com
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发表时间：
2007-09-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Hongjun
中科院分区：
文献类型：
--
作者：
Goldberg, Alyssa;Parolini, Margherita;Wang, Hongjun
胰岛供体暴露于一氧化碳（CO）常常导致受体胰岛移植物长期存活和耐受。我们在此表明，CO至少部分通过抑制胰腺β细胞中Toll样受体4（TLR 4）的上调来赋予其保护作用。在分离过程中，TLR 4在胰岛中通常上调;用CO处理供体抑制分离的胰岛以及移植的移植物中的TLR 4表达。TLR 4上调允许引发炎症，这导致胰岛同种异体移植物排斥;来自TLR 4缺陷小鼠的胰岛移植物在BALB/ c受体中无限期存活，并且与来自对照供体的移植物相比，在移植后的不同天数显示出显著更少的炎症。移植前用TLR 4显性阴性病毒预感染的孤立胰岛在受体中表现出延长的存活。尽管TLR 4抑制的有益效果，HO- 1的表达仍然需要在受体胰岛的生存：TLR 4缺陷的胰岛移植到受体后，立即拒绝HO- 1活性被阻断。此外，胰岛素瘤细胞系β TC 3与抗TLR 4抗体的孵育保护这些细胞免于细胞因子诱导的细胞凋亡。我们的数据表明，β细胞中的TLR 4诱导参与移植后的β细胞死亡和移植物排斥。CO暴露通过阻断TLR 4上调保护胰岛免受排斥。
Carbon monoxide ( CO) exposure of an islet donor frequently leads to islet allograft long- term survival and tolerance in recipients. We show here that CO confers its protective effects at least in part by suppressing Toll- like receptor 4 ( TLR4) up- regulation in pancreatic beta cells. TLR4 is normally up- regulated in islets during the isolation procedure; donor treatment with CO suppresses TLR4 expression in isolated islets as well as in transplanted grafts. TLR4 up- regulation allows initiation of inflammation, which leads to islet allograft rejection; islet grafts from TLR4- deficient mice survive indefinitely in BALB/ c recipients and show significantly less inflammation at various days after transplantation compared with grafts from a control donor. Isolated islets preinfected with a TLR4 dominant negative virus before transplantation demonstrated prolonged survival in recipients. Despite the salutary effects of TLR4 suppression, HO- 1 expression is still needed in the recipient for islet survival: TLR4deficient islets were rejected promptly after being transplanted into recipients in which HO- 1 activity was blocked. In addition, incubation of an insulinoma cell line, beta TC3, with an anti- TLR4 antibody protects those cells from cytokine- induced apoptosis. Our data suggest that TLR4 induction in beta cells is involved in beta cell death and graft rejection after transplantation. CO exposure protects islets from rejection by blocking TLR4 up- regulation.