Lewis Eli C, Dinarello Charles A
Department of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16852-7. doi: 10.1073/pnas.0607917103. Epub 2006 Oct 30.
Pancreatic islets contain cells that produce IL-18 and cells that express IL-18 receptors. In experimentally induced diabetes, islet failure correlates with IL-18 levels and diabetes is delayed with blockade of endogenous IL-18. We studied islet-derived IL-18 and responses to IL-18 in a mouse model of islet allograft transplantation. In vitro, IL-18-stimulated islets produced nitric oxide, which closely matched islet apoptosis. By neutralizing IL-18 activity with IL-18 binding protein (IL-18BP), we observed that islets produce bioactive IL-18. In vivo, transgenic mice overproducing IL-18BP (IL-18BP-Tg) exhibited delayed hyperglycemia induced by beta cell toxic streptozotocin. Similarly, cultured IL-18BP-Tg islets were protected from streptozotocin-induced apoptosis. In the transplant model, islets grafted from WT to IL-18BP-Tg mice achieved prolonged normoglycemia (P = 0.031). Improved graft function was also observed by using IL-18-deficient islets transplanted into WT recipients, demonstrating that endogenous, islet-derived IL-18 mediates IL-18-driven graft damage. Unexpectedly, islets from mice deficient in IL-18 receptor alpha chain (IL-18R) exhibited rapid graft failure (P = 0.024; IL-18- versus IL-18R-deficient grafts in WT recipients). In related studies, IL-18R-deficient splenocytes and macrophages produced 2- to 3-fold greater amounts of IL-18, TNFalpha, macrophage inflammatory protein 1, macrophage inflammatory protein 2, and IFNgamma upon stimulation with Con A, Toll-like receptor 2 agonist, or anti-CD3 antibodies. These data reveal a role for islet-derived IL-18 activity during inflammation-mediated islet injury. Importantly, discrepancies between IL-18- and IL-18R-deficient cells suggest that IL-18Ralpha chain is used by an inflammation-suppressing signal.
胰岛包含产生白细胞介素-18（IL-18）的细胞以及表达IL-18受体的细胞。在实验性诱导的糖尿病中，胰岛功能衰竭与IL-18水平相关，并且通过阻断内源性IL-18可延缓糖尿病的发生。我们在胰岛同种异体移植的小鼠模型中研究了胰岛来源的IL-18以及对IL-18的反应。在体外，IL-18刺激的胰岛产生一氧化氮，这与胰岛凋亡密切相关。通过用IL-18结合蛋白（IL-18BP）中和IL-18活性，我们观察到胰岛产生具有生物活性的IL-18。在体内，过量产生IL-18BP的转基因小鼠（IL-18BP-Tg）表现出由β细胞毒性链脲佐菌素诱导的高血糖延迟。同样，培养的IL-18BP-Tg胰岛受到保护，免受链脲佐菌素诱导的凋亡。在移植模型中，从野生型（WT）小鼠移植到IL-18BP-Tg小鼠的胰岛实现了延长的正常血糖水平（P = 0.031）。通过将IL-18缺陷型胰岛移植到WT受体中也观察到移植功能得到改善，这表明内源性的、胰岛来源的IL-18介导了IL-18驱动的移植损伤。出乎意料的是，缺乏IL-18受体α链（IL-18R）的小鼠的胰岛表现出快速的移植失败（P = 0.024；WT受体中IL-18缺陷型与IL-18R缺陷型移植）。在相关研究中，缺乏IL-18R的脾细胞和巨噬细胞在用刀豆蛋白A、Toll样受体2激动剂或抗CD3抗体刺激后，产生的IL-18、肿瘤坏死因子α（TNFα）、巨噬细胞炎性蛋白1、巨噬细胞炎性蛋白2和干扰素γ（IFNγ）的量增加2至3倍。这些数据揭示了胰岛来源的IL-18活性在炎症介导的胰岛损伤中的作用。重要的是，IL-18缺陷型细胞与IL-18R缺陷型细胞之间的差异表明，IL-18Rα链被一种炎症抑制信号所利用。
