Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1.
Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1.
复制标题
白介素1刺激β细胞坏死和免疫辅助HMGB1的释放。
DOI：
10.1371/journal.pmed.0030017
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发表时间：
2006-02
期刊：
影响因子：
15.8
通讯作者：
Corbett, JA
中科院分区：
文献类型：
--
作者：
Steer, SA;Scarim, AL;Chambers, KT;Corbett, JA
在自身免疫性糖尿病的发展过程中，β细胞的死亡至少有两个阶段：一个是导致β细胞特异性抗原释放的起始事件，另一个是抗原驱动的事件，在这个事件中，β细胞的死亡通过T淋巴细胞的作用而介导。本文对巨噬细胞来源的细胞因子白介素1诱导β细胞死亡的机制进行了研究。已知的IL-1通过刺激诱导型一氧化氮合酶的表达和增加β细胞产生一氧化氮来抑制葡萄糖诱导的胰岛素分泌，也可以诱导β细胞死亡。为了确定细胞死亡的机制，我们检测了IL-1和已知的凋亡激活剂对β-细胞活力的影响。当IL-1刺激β-细胞的DNA损伤时，这种细胞因子不能激活caspase-3或诱导磷脂酰丝氨酸(PS)外化，但凋亡诱导剂激活caspase-3和PS在β-细胞上的外化。相反，IL-1以一氧化氮依赖的方式刺激免疫佐剂高迁移率族蛋白1(HMGB1；坏死的生化标记物)的释放，而凋亡诱导剂不能刺激HMGB1的释放。经IL-1处理的β细胞释放HMGB1对半胱氨酸天冬氨酸氨基转移酶-3的抑制不敏感，而抑制半胱氨酸天冬氨酸氨基转移酶可减轻β细胞对已知的凋亡诱导剂的反应。1型糖尿病(也称为自身免疫性糖尿病或青少年糖尿病)是一种自身免疫性疾病。由于未知的原因，在童年或青春期的某个时候，人体自身的免疫系统开始攻击和破坏胰腺中产生胰岛素的胰岛细胞。一旦大多数胰岛细胞被破坏，患者就不能再产生胰岛素来调节血糖，必须依靠严格的饮食和胰岛素注射。科学家们正试图了解这种疾病发展过程中的早期事件。在高等动物和人类的细胞中，有两种根本不同的细胞死亡，称为凋亡和坏死。细胞凋亡(也称为程序性细胞死亡)是一种有组织的、干净的方式，细胞在不溢出其内容物的情况下死亡，也不会引起炎症免疫反应。它们只是被充当身体垃圾收集器的其他细胞吞噬。另一方面，坏死是一个更混乱的过程，它确实会激活免疫系统，导致局部炎症。做这项研究的科学家对胰岛细胞死亡的早期阶段很感兴趣。具体地说，他们想知道在自身免疫性糖尿病的早期事件中，胰岛细胞是通过凋亡还是坏死而死亡。解决这个问题的早期实验并没有产生明确的结果。本研究的所有实验都是在实验室培养的细胞中进行的。在很大程度上，研究人员使用了啮齿动物的胰岛细胞，然后他们证实了在人类胰岛细胞中的关键发现。据他们所知，他们在与糖尿病早期相似的条件下培养细胞，糖尿病导致一些细胞死亡。然后，他们进行了各种测试，以确定细胞死亡是通过细胞凋亡还是通过坏死来实现的，结果表明是后者。他们还确定了促进和执行坏死过程的一些关键因素。人们必须始终小心地从这样的实验室结果中进行推断。有了这一警告，结果表明，在糖尿病发展的早期，细胞会因坏死而死亡，他们指出了其中一些关键因素。这些都是重要的结果，将为未来的研究提供信息，目标是充分了解自身免疫性糖尿病，以预防或阻止其发展。以下网站提供了有关自身免疫性糖尿病的信息。1型糖尿病的MedlinePlus页面：青少年糖尿病研究基金会的http://www.nlm.nih.gov/medlineplus/ency/article/000305.htm网站：加拿大糖尿病协会的http://www.jdrf.org/index.cfm?page_id=101982 1型糖尿病页面：英国国家健康和临床卓越研究所的http://www.diabetes.ca/Section_About/type1.asp 1型糖尿病页面：http://www.nice.org.uk/page.aspx?o=213575英国国家糖尿病信息中心：http://diabetes.niddk.nih.gov/index.htm美国糖尿病协会网站：http://www.diabetes.org这些发现表明，IL-1导致β细胞坏死，并支持这样的假设，即巨噬细胞衍生的细胞因子可能通过促进抗原释放(坏死)和胰岛炎症(HMGB1释放)的机制诱导β细胞死亡，从而参与糖尿病发展的初期阶段。来自啮齿动物和人类细胞的结果表明，β细胞的坏死在1型糖尿病的早期阶段发挥了作用。
There are at least two phases of β-cell death during the development of autoimmune diabetes: an initiation event that results in the release of β-cell-specific antigens, and a second, antigen-driven event in which β-cell death is mediated by the actions of T lymphocytes. In this report, the mechanisms by which the macrophage-derived cytokine interleukin (IL)-1 induces β-cell death are examined. IL-1, known to inhibit glucose-induced insulin secretion by stimulating inducible nitric oxide synthase expression and increased production of nitric oxide by β-cells, also induces β-cell death. To ascertain the mechanisms of cell death, the effects of IL-1 and known activators of apoptosis on β-cell viability were examined. While IL-1 stimulates β-cell DNA damage, this cytokine fails to activate caspase-3 or to induce phosphatidylserine (PS) externalization; however, apoptosis inducers activate caspase-3 and the externalization of PS on β-cells. In contrast, IL-1 stimulates the release of the immunological adjuvant high mobility group box 1 protein (HMGB1; a biochemical maker of necrosis) in a nitric oxide-dependent manner, while apoptosis inducers fail to stimulate HMGB1 release. The release of HMGB1 by β-cells treated with IL-1 is not sensitive to caspase-3 inhibition, while inhibition of this caspase attenuates β-cell death in response to known inducers of apoptosis. Type 1 diabetes (also called autoimmune diabetes or juvenile diabetes) is an autoimmune disease. For unknown reasons, at some point in childhood or adolescence, the body's own immune system starts attacking and destroying the insulin-producing islet cells in the pancreas. Once the majority of islet cells are destroyed, patients can no longer produce insulin to regulate their blood sugar and must depend on strict diets and insulin injections. Scientists are trying to understand the early events during the development of the disease. There are two fundamentally different kinds of cell death in cells of higher animals and humans, called apoptosis and necrosis. Apoptosis (also called programmed cell death) is an organized, clean way in which cells die without spilling their contents and without causing an inflammatory immune response. They are simply gobbled up by other cells that serve as the body's garbage collectors. Necrosis, on the other hand, is a more messy process and one that does activate the immune system and cause local inflammation. The scientists who did this study are interested in the early stages of islet cell death. Specifically, they wanted to know whether islet cells during the early events of autoimmune diabetes die via apoptosis or necrosis. Earlier experiments to address this question had yielded no clear-cut results. All the experiments for this study were done in cultured cells in the laboratory. For the most part, the researchers used rodent islet cells, and then they confirmed the crucial finding in human islet cells. They grew the cells under conditions that resembled, to the best of their knowledge, the early stages of diabetes, which caused some of the cells to die. They then did a variety of tests to see whether that cell death was through apoptosis or necrosis, and the results showed that the latter was the case. They also identified some of the key factors involved in promoting and executing the necrosis process. One must always be careful to extrapolate from laboratory results like these. With this caveat, the results suggest that early in the development of diabetes cells die by necrosis, and they point to some of the key factors involved. These are important results that will inform future studies toward the goal of understanding autoimmune diabetes well enough to prevent or stop its development. The following Web sites provide information on autoimmune diabetes. MedlinePlus pages on type 1 diabetes: http://www.nlm.nih.gov/medlineplus/ency/article/000305.htm Web site of the Juvenile Diabetes Research Foundation: http://www.jdrf.org/index.cfm?page_id=101982 Pages on type 1 diabetes from the Canadian Diabetes Association: http://www.diabetes.ca/Section_About/type1.asp Type 1 diabetes pages from the UK National Institute for Health and Clinical Excellence: http://www.nice.org.uk/page.aspx?o=213575 UK National Diabetes Information Clearinghouse: http://diabetes.niddk.nih.gov/index.htm American Diabetes Association Web site: http://www.diabetes.org These findings indicate that IL-1 induces β-cell necrosis and support the hypothesis that macrophage-derived cytokines may participate in the initial stages of diabetes development by inducing β-cell death by a mechanism that promotes antigen release (necrosis) and islet inflammation (HMGB1 release). Results from rodent and human cells suggest that necrosis of β-cells plays a role in the early stages of type 1 diabetes.
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影响因子：
7.7
作者：
Chen, GX;Hohmeier, HE;Newgard, CB
通讯作者：
Newgard, CB
影响因子：
2.9
作者：
GREEN, LC;WAGNER, DA;TANNENBAUM, SR
通讯作者：
TANNENBAUM, SR
影响因子：
4.8
作者：
Heitmeier, MR;Scarim, AL;Corbett, JA
通讯作者：
Corbett, JA
影响因子：
7.7
作者：
Eizirik, DL;Darville, MI
通讯作者：
Darville, MI
DOI：
10.1073/pnas.90.5.1731
发表时间：
1993-03-01
影响因子：
11.1
作者：
CORBETT, JA;SWEETLAND, MA;MCDANIEL, ML
通讯作者：
MCDANIEL, ML