Regulation of macrophage interleukin-1 beta production

描述(申请人提供)：肺部，经常暴露 对环境病原体来说，肺泡巨噬细胞是最前线的 防守。它应对入侵微生物的能力对宿主来说至关重要 生死存亡。由组织巨噬细胞释放的促炎细胞因子提供 参与宿主防御的早期信号分子。表达不足 IL-1β等细胞因子可导致压倒性感染和死亡，而 这些分子的过度表达会导致组织损伤和成人 呼吸窘迫综合征。从而更好地了解IL-1β 生理学是理解肺宿主防御和肺损伤的关键。 处理和释放IL-1β的能力是一项关键的免疫功能 肺巨噬细胞。然而，尽管来自以下方面的巨大见解 半胱氨酸天冬氨酸氨基转移酶的原型--IL-1转换酶的发现 凋亡酶家族，对其如何失活知之甚少 IL-1β的前体由ICE(caspase-1)处理。此外， 信号肽和前导序列缺陷的IL-1β的释放途径 尚未被发现。因此，这项建议的主要重点是 直指这个问题。我们将检验这样的假设：激活事件 (通过Toll样受体)诱导多组分的组织 蛋白质复合体。这种蛋白复合体诱导ICE和Places的激活 它和IL-1胎儿转化为一种释放调节蛋白的复合体 协调成熟的细胞因子输出。 在这种情况下，我们最近有证据支持这样的假设 IL-1β的处理和释放由一种蛋白质复合体(即 我们称之为ICEasome)，它与核因子-kB有重要联系 信号体。我们认为ICE和新的IL-1释放调节分子 (最近通过酵母双杂交筛选鉴定)与Toll-like连锁 I-kB激酶复合体激活受体及其调控 蛋白酶体介导的蛋白质降解。该提案的具体目的是寻求 为了检验IL-1β的释放依赖于ICE的假设， 不依赖于它的转换酶活性。冰可能在一定程度上通过它的 形成卡片-卡片相互作用的能力，将IL-1β与核因子-kB途径联系起来。 我们进一步提出，IL-1β的释放在某种程度上是负调控的 类似于I-kBalpha对核因子-kB的调节。我们假设《邮件》是一部小说 酵母双杂交筛选发现的I-kBalpha蛋白同源物 负向调节Proll-1β的处理和释放。

DESCRIPTION (provided by applicant): In the lung, which is constantly exposed to environmental pathogens, the alveolar macrophage represents the front line defense. Its ability to cope with invading microorganisms is critical to host survival. Proinflammatory cytokines released by tissue macrophages provide the early signaling molecules that gamer the host defenses. Underexpression of cytokines like IL-1beta can lead to overwhelming infection and death whereas overexpression of these molecules can lead to tissue injury and the adult respiratory distress syndrome. Thus a better understanding of IL-1 beta physiology is critical to understanding lung host defense and lung injury. The ability to process and release IL-1beta is a key immune function of the lung macrophage. However, despite the tremendous insights that have come from the discovery of IL-1 converting enzyme (ICE), the prototype of the caspase family of apoptotic enzymes, very little is known about how the inactive precursor for IL-1beta is processed by ICE (caspase-1). Furthermore, the release pathway used by signal peptide- and leader sequence-deficient IL-1beta has yet to be discovered. Therefore, the major emphasis of this proposal is directed at this question. We will test the hypothesis that activation events (occurring via Toll-like receptors) induce the organization of a multicomponent protein complex. This protein complex induces the activation of ICE and places it and IL-1 feta into a composite of release-regulating proteins that orchestrate mature cytokine export. In this context, we have recent evidence to support the hypothesis that IL-1beta processing and release is controlled by a complex of proteins (which we have termed the ICEasome) that has significant links to the NF-kB signalosome. We propose that ICE and novel IL-1 release-regulating molecules (recently identified by yeast two-hybrid screening) are linked to Toll-like receptor activation by complexes with I-kB kinases and by regulation through proteasome-mediated protein degradation. The specific aims of the proposal seek to test the hypothesis that IL-1beta release depends upon ICE in a manner that is independent of its convertase activity. ICE may function in part by its ability to form CARD-CARD interactions that link IL-1beta to the NF-kB pathway. We further propose that IL-1beta release is negatively regulated in a manner analogous to NF-kB's regulation by I-kBalpha. We hypothesize that MAIL, a novel protein homologue of I-kBalpha that we discovered by yeast two-hybrid screening negatively regulates prolL-1beta processing and release.