α1-antitrypsin increases interleukin-1 receptor antagonist production during pancreatic islet graft transplantation
α1-antitrypsin increases interleukin-1 receptor antagonist production during pancreatic islet graft transplantation
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DOI：
10.1038/cmi.2014.17
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发表时间：
2014-07-01
影响因子：
24.1
通讯作者：
Lewis, Eli C.
中科院分区：
文献类型：
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作者：
Abecassis, Avishag;Schuster, Ronen;Lewis, Eli C.
虽然胰岛移植对1型糖尿病患者有较好的血糖控制效果，但长期控制仍不充分。部分原因是胰岛损伤和压力会导致β细胞损失。抑制过量的IL-1 β活性可能会减少胰岛损伤，从而保持功能。IL-1受体拮抗剂（IL-1Ra）是一种内源性IL-1 β抑制剂，可保护胰岛免受细胞因子诱导的坏死和凋亡。因此，IL-1 β和IL-1Ra之间的不平衡可能会影响对胰岛的异体和自身免疫反应的过程。我们的团队先前证明了循环丝氨酸蛋白酶抑制剂人类α -1-抗胰蛋白酶（hAAT），其水平在急性期免疫反应中增加，具有抗炎和胰岛保护特性，以及免疫调节活性。在本研究中，我们试图确定hAAT的胰岛同种异体移植物保护活性是否由IL-1Ra诱导介导。我们的研究结果表明，hAAT导致受刺激的巨噬细胞IL-1Ra表达增加2.04倍，hAAT预处理的胰岛移植物IL-1Ra转录水平增加4.851倍，这与中度炎症相关。出乎意料的是，从IL-1Ra敲除小鼠中分离出来的胰岛，在移植到野生型小鼠之前用hAAT预处理，结果显示，尽管没有对宿主进行hAAT处理，但植入的IL-1Ra表达增加，这可能是来自于浸润宿主细胞。事实上，经haat预处理的胰岛产生的无haat条件培养基可以诱导培养巨噬细胞产生IL-1Ra。最后，我们证明hAAT促进了p65的独特磷酸化和核易位模式，p65是IL-1Ra表达所需的关键转录因子。
Although islet transplantation for individuals with type 1 diabetes has been shown to yield superior blood glucose control, it remains inadequate for long-term control. This is partly due to islet injuries and stresses that can lead to beta cell loss. Inhibition of excess IL-1 beta activity might minimize islet injuries, thus preserving function. The IL-1 receptor antagonist (IL-1Ra), an endogenous inhibitor of IL-1 beta, protects islets from cytokine-induced necrosis and apoptosis. Therefore, an imbalance between IL-1 beta and IL-1Ra might influence the courses of allogeneic and autoimmune responses to islets. Our group previously demonstrated that the circulating serine-protease inhibitor human alpha-1-antitrypsin (hAAT), the levels of which increase in circulation during acute-phase immune responses, exhibits anti-inflammatory and islet-protective properties, as well as immunomodulatory activity. In the present study, we sought to determine whether the pancreatic islet allograft-protective activity of hAAT was mediated by IL-1Ra induction. Our results demonstrated that hAAT led to a 2.04-fold increase in IL-1Ra expression in stimulated macrophages and that hAAT-pre-treated islet grafts exhibited a 4.851-fold increase in IL-1Ra transcript levels, which were associated with a moderate inflammatory profile. Unexpectedly, islets that were isolated from IL-1Ra-knockout mice and pre-treated with hAAT before grafting into wild-type mice yielded an increase in intragraft IL-1Ra expression that was presumably derived from infiltrating host cells, albeit in the absence of hAAT treatment of the host. Indeed, hAAT-pre-treated islets generated hAAT-free conditioned medium that could induce IL-1Ra production in cultured macrophages. Finally, we demonstrated that hAAT promoted a distinct phosphorylation and nuclear translocation pattern for p65, a key transcription factor required for IL-1Ra expression.