...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The Internet Journal of Asthma, Allergy and Immunology >Leukotriene Synthesis by Epithelial Cells of Human Mucosa-Associated Lymphoid Tissue
【24h】

Leukotriene Synthesis by Epithelial Cells of Human Mucosa-Associated Lymphoid Tissue

机译：人黏膜相关淋巴组织的上皮细胞合成白三烯

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Lymphocyte activation and immunoglobulin synthesis are key events in acquired immunity. Leukotrienes are lipid mediators known to modulate these events in vitro, but how they might directly interact with lymphocytes in vivo has been unclear. The enzyme 5-lipoxygenase catalyzes the rate-limiting steps in leukotriene synthesis. Here we report that 5-lipoxygenase protein was found in abundance in epithelial cells of human mucosa-associated lymphoid tissue. In addition, leukotriene A4 hydrolase and the 5-lipoxygenase activating protein were also present in lymphoid tissue epithelium, indicating that these cells should be able to independently metabolize arachidonic acid to leukotrienes. Indeed, epithelium-rich tissue fractions were capable of synthesizing both leukotriene B4 and 5-hydroxyeicosatetraenoic acid from arachidonic acid. The abundance of 5-lipoxygenase protein, the amount of leukotriene B4 secreted, and the extent of epithelium stratification differed between samples from different donors. Together, these results place leukotriene synthesis in an unexpected site, mucosa-associated lymphoid tissue epithelium, where secreted leukotrienes may affect lymphocyte activation and immunoglobulin synthesis. Dysregulation of leukotriene synthesis in this context, in turn, may be relevant to asthma, allergic response, and autoimmune disorders. Abbreviations: AA, arachidonic acid; DAB, 3,3'-diaminobenzidine; FLAP, 5-lipoxygenase activating protein; HETE, hydroxyeicosatetraenoic acid; Ig, immunoglobulin; 5-LO, 5-lipoxygenase; LT, leukotriene; MALT, mucosa-associated lymphoid tissue; RBL, rat basophilic leukemia. Introduction Leukotrienes (LTs) are lipid mediators that play pivotal roles in normal immune defense. However, the overproduction of LTs contributes to several diseases, including asthma (1,2) and allergic response (3, 4, 5). In particular, the cysteinyl LTs, LTC4 and LTD4, trigger the classic symptoms of asthma and allergic hyperresponsiveness, including bronchoconstriction, edema, and mucus secretion (6,7). LTB4 is best known as a promoter of leukocyte recruitment (8) and activation (9) and is thought to contribute to the chronic inflammation that can occur in the asthmatic patient. Pharmaceuticals that modify the action of LTs, particularly of the cysteinyl LTs, are efficacious in ameliorating these symptoms and are currently used in the treatment of asthma.LTs are synthesized enzymatically from arachidonic acid (AA). The synthesis of LTs is initiated by the action of 5-lipoxygenase (5-LO) (10) in concert with the 5-lipoxygenase activating protein (FLAP) (11,12). Leukotriene A4, generated by the oxygenation of AA by 5-LO, may be converted either to LTB4 by the enzyme LTA4 hydrolase, or to LTC4 via LTC4 synthase.As suggested by their name, LTs are synthesized primarily by leukocytes, especially those of the myeloid lineage. Non-leukocytes, including epithelial cells, may contain FLAP protein and either LTA4 hydrolase or LTC4 synthase, but characteristically lack 5-LO protein (13, 14, 15). As a result, these cells cannot independently synthesize either LTB4 or LTC4. However, it is well established that epithelial cells can synthesize LTs by a transcellular pathway by metabolizing LTA4 released from neighboring leukocytes (16, 17, 18).Several studies have demonstrated that LTB4 can stimulate B lymphocytes and enhance IL-4-mediated IgG, IgM and IgE synthesis (19, 20, 21), as well as modulate T cell proliferation (22, 23, 24, 25, 26, 27) and IL-2 synthesis (28,29). More recently, Irvin and colleagues found that 5-LO knockout mice showed a diminished capacity to generate immunoglobulin (Ig) E or antigen-specific IgG following antigen exposure (30). Also, the spleens of 8-week-old mice lacking a functional 5-LO gene were 20% smaller than those of wild type mice (31). Although LTs can clearly affect lymphocytes in vitro, it is unclear how lymphocytes might directly encounter these paracrine mediators in vivo.The upper airway is a
机译：淋巴细胞激活和免疫球蛋白合成是获得性免疫中的关键事件。白三烯是脂质介体，可在体外调节这些事件，但尚不清楚它们如何与体内淋巴细胞直接相互作用。 5-脂氧合酶催化白三烯合成中的限速步骤。在这里，我们报告在人类黏膜相关淋巴组织的上皮细胞中大量发现5-脂氧合酶蛋白。此外，淋巴组织上皮细胞中也存在白三烯A4水解酶和5-脂氧合酶激活蛋白，表明这些细胞应能够独立地将花生四烯酸代谢为白三烯。实际上，富含上皮的组织级分能够从花生四烯酸合成白三烯B4和5-羟基二十碳四烯酸。不同供体的样品中5-脂氧合酶蛋白的丰度，分泌的白三烯B4的量以及上皮分层的程度有所不同。总之，这些结果将白三烯合成置于意想不到的位置，即与粘膜相关的淋巴样组织上皮，其中分泌的白三烯可能影响淋巴细胞的活化和免疫球蛋白的合成。在这种情况下，白三烯合成失调可能与哮喘，过敏反应和自身免疫性疾病有关。缩写：AA，花生四烯酸; DAB，3,3'-二氨基联苯胺; FLAP，5-脂氧合酶激活蛋白; HETE，羟基二十碳四烯酸; Ig，免疫球蛋白; 5-LO，5-脂氧合酶; LT，白三烯; MALT，粘膜相关淋巴组织; RBL，大鼠嗜碱性白血病。简介白三烯（LTs）是脂质介体，在正常的免疫防御中起关键作用。但是，LTs的过度生产会导致多种疾病，包括哮喘（1,2）和过敏反应（3，4，5）。特别是，半胱氨酰LTs，LTC4和LTD4引发哮喘和过敏性高反应性的典型症状，包括支气管收缩，浮肿和粘液分泌（6,7）。 LTB4是白细胞募集（8）和激活（9）的启动子，众所周知，它可导致哮喘患者发生慢性炎症。改变LT尤其是半胱氨酸LT的作用的药物可有效缓解这些症状，目前用于哮喘的治疗。LT是由花生四烯酸（AA）酶促合成的。 LT的合成是由5-脂氧合酶（5-LO）（10）与5-脂氧合酶激活蛋白（FLAP）共同作用（11,12）引发的。由5-LO氧化AA产生的白三烯A4可以通过LTA4水解酶转化为LTB4，也可以通过LTC4合酶转化为LTC4，正如其名称所暗示的那样，LT主要由白细胞合成，特别是白细胞。骨髓谱系。非白细胞，包括上皮细胞，可能含有FLAP蛋白和LTA4水解酶或LTC4合酶，但特征是缺乏5-LO蛋白（13、14、15）。结果，这些单元不能独立地合成LTB4或LTC4。然而，众所周知，上皮细胞可以通过代谢从邻近白细胞释放的LTA4，通过跨细胞途径合成LT（16、17、18）。多项研究表明，LTB4可以刺激B淋巴细胞并增强IL-4介导的IgG， IgM和IgE合成（19，20，21），以及调节T细胞增殖（22，23，24，25，26，27）和IL-2合成（28,29）。最近，Irvin及其同事发现，敲除5-LO的小鼠在暴露于抗原后产生免疫球蛋白（Ig）E或抗原特异性IgG的能力降低（30）。同样，缺少功能性5-LO基因的8周龄小鼠的脾脏比野生型小鼠的脾脏小20％（31）。尽管LTs可以在体外明显影响淋巴细胞，但尚不清楚淋巴细胞如何在体内直接遇到这些旁分泌介质。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号