Biogenesis of IL-1a in inflammatory process

摘要 IL-1/IL-1 RI信号传导是通过炎症驱动正常组织中稳态失调的关键， 一种造血起源的特化细胞的募集和保留过程，其可能并且通常确实 导致受影响器官的生理功能中断。今天，发病机制的广大 大多数人类疾病都与急性或慢性炎症有关， 稳态失调，在机制上是许多和特定疾病驱动病理的基础。白介素- 1 RI信号传导在受体IL-1α的两个主要非同源配体中的任一个结合时启动 或IL-1β。在过去的十年中，在理解IL-1β的生物学方面取得了真正显著的进展 由于发现半胱天冬酶-1依赖性炎性小体和半胱天冬酶-8作为IL-1β的调节剂， 生物起源与IL-1β形成鲜明对比，并且尽管是描述的第一个主要的人类热原（Dinarello et 例如，1974），IL-1α的生物起源仍然知之甚少。此外，尽管人们越来越认识到， IL-1α在许多重要的人类疾病发病机制中的作用， 功能性IL-1α成熟仍然完全不清楚。这项探索性赠款提案的目标是确定 IL-1α前体的特异性分子修饰，使IL-1α在其膜中具有生理功能， 结合和分泌形式。在具体目标1中，我们将定义特定翻译后蛋白的功能作用。 修饰pro-IL-1α以诱导IL-1α作为分泌的和膜结合的细胞因子的生物活性， 体外在具体目标2中，我们将定义IL-1α的分子形式，在炎症中触发炎症性IL-1 RI信号传导。 对病毒和细菌病原体的反应以及体内细胞毒性损伤。这些研究应该有助于制定一个 IL-1α生物发生的统一概念模型，使保护性和病理性IL-1α驱动的宿主 对病原体、压力和无菌损伤的反应。这些研究有可能改变目前的- 接受IL-1β为中心的炎症范式，以IL-1α依赖性促炎启动的概念， 损伤或感染的部位，作为大量人类炎症的引发者和维持者， 疾病

ABSTRACT IL-1/IL-1RI signaling is pivotal for driving dysregulation of homeostasis in normal tissues through inflammation, a process of recruitment and retention of specialized cells of hematopoietic origin, which may and often does lead to the disruption of physiological function of the affected organ. Today, the pathogenesis of the vast majority of human diseases has been linked to the acute or chronic inflammation as the key components of homeostatic dysregulation, mechanistically underlying numerous and specific disease-driving pathologies. IL- 1RI signaling is initiated upon binding of either of two principal non-homologous ligands of the receptor – IL-1α or IL-1β. Over the past decade, truly remarkable progress has been made in understanding the biology of IL-1β due to the discovery of the caspase-1-dependent inflammasome(s) and caspase-8 as regulators of IL-1β biogenesis. In stark contrast to IL-1β, and despite being the first major human pyrogen described (Dinarello et al., 1974), the biogenesis of IL-1α remains poorly understood. Furthermore, despite increasing appreciation of the contribution of IL-1α in the pathogenesis of many important human diseases, the factors that control functional IL-1α maturation remain completely obscure. The goal of this exploratory grant proposal is to identify specific molecular modifications of IL-1α precursor that enable physiological IL-1α function in its membrane- bound and secreted forms. In Specific Aim 1, we will define the functional role of specific post-translational modifications of pro-IL-1α for eliciting IL-1α biological activity as secreted and membrane-bound cytokines in vitro. In Specific Aim 2, we will define molecular forms of IL-1α, triggering inflammatory IL-1RI signaling in response to viral and bacterial pathogens and cytotoxic injury in vivo. These studies should aid in developing a unifying conceptual model of biogenesis of IL-1α that enables protective and pathologic IL-1α-driven host responses to pathogens, stress, and sterile injury. These studies have the potential to shift the currently- accepted IL-1β-centric paradigm of inflammation to a concept of IL-1α-dependent pro-inflammatory priming at a site of injury or infection as the initiator and sustainer of inflammation underlying a great number of human diseases.