Regulation of macrophage interleukin-1 beta production

描述（由申请人提供）：在肺中，持续暴露 对于环境病原体，肺泡巨噬细胞代表了前线 防御它科普入侵微生物的能力对宿主至关重要 生存组织巨噬细胞释放的促炎细胞因子提供了 增强宿主防御的早期信号分子。的低表达 IL-1 β等细胞因子可导致严重感染和死亡， 这些分子的过度表达可导致组织损伤， 呼吸窘迫综合征因此，更好地了解IL-1 β 生理学对于理解肺宿主防御和肺损伤至关重要。 处理和释放IL-1 β的能力是免疫系统的关键免疫功能。 肺巨噬细胞然而，尽管有来自 IL-1转化酶（ICE）的发现，caspase的原型 凋亡酶家族，很少有人知道如何失活 IL-1 β的前体由ICE（半胱天冬酶-1）加工。而且 信号肽和前导序列缺陷型IL-1 β释放途径 尚未被发现。因此，这项建议的重点是 针对这个问题。我们将检验激活事件 （通过Toll样受体发生）诱导多组分 蛋白质复合物这种蛋白质复合物诱导ICE的活化， 它和IL-1 feta合成一种释放调节蛋白的复合物， 协调成熟细胞因子输出。 在这方面，我们最近有证据支持这样的假设， IL-1 β的加工和释放是由一种蛋白质复合物控制的（ 我们称之为ICEasome），它与NF-κ B有着重要的联系， 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样 通过与I-kB激酶的复合物和通过调节受体活化 蛋白酶体介导的蛋白质降解。该提案的具体目标是 为了检验IL-1 β释放依赖于ICE的假设， 与其转化酶活性无关。ICE可以部分地通过其 能够形成CARD-CARD相互作用，将IL-1 β与NF-κ B通路连接起来。 我们进一步提出，IL-1 β的释放是负调控的方式， 类似于I-kB α对NF-κ B的调节。我们假设一部小说《邮件》 我们通过酵母双杂交筛选发现了I-kB α的蛋白质同源物 负调节prolL-1 β的加工和释放。

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.