Mechanism of 4-1BBL-mediated sustained inflammation: target of anti-inflammation

描述（由申请人提供）：炎症是一种有益的反应，用于限制细胞和器官损伤，以保护身体免受感染或移除受损组织，炎症反应调节的破坏可能导致广泛的炎症性疾病。先天免疫细胞对微生物感染和细胞损伤立即作出反应，启动炎症反应，并且反应可以延长一段时间。巨噬细胞持续产生细胞因子有助于体内炎症的延长。我们的初步研究表明，诱导细胞表面4-1BB配体（4-1BBL）是巨噬细胞持续产生TNF的必要条件。这种信号机制是顺序发生的；4-1BBL在初始阶段以TLR通路依赖的方式被诱导，并在后期转运到细胞表面与TLR形成复合物以激活下游信号。抑制后期次级信号通路导致炎症反应减少，这表明4-1BBL信号是抗炎症治疗的潜在靶点。然而，在控制TNF产生的初始和继发性信号通路中仍有缺失的步骤，其在炎症性疾病中的相关性尚不清楚。因此，我们假设4-1BBL的表达是由tlr特异性信号通路介导的，诱导了一种新的第二信号机制来维持炎症反应。我们提出以下具体目标来检验我们的假设。在Aim 1中，我们将重点研究4- 1bbl介导的TNF产生的信号机制，如信号分子在4- 1bbl介导的次级信号通路中的参与和相互作用。在Aim 2中，我们将研究4-1BBL在TLR介导的信号通路中的表达机制，以确定4-1BBL在TLR信号通路中炎症反应中的特异性。Aim 3的重点是通过阻断4-1BBL介导的信号通路来抑制炎症反应，从而减少持续的炎症反应。本提案中的研究将回答如何调节炎症的基本问题。从这些研究中获得的知识将扩展到生物学研究，并将有助于开发新的抗炎疗法的新策略。

DESCRIPTION (provided by applicant): Inflammation is a beneficial response in limiting cellular and organ damages to protect a body from an infection or to remove the damaged tissues, and that a breakdown in the regulation of the inflammatory responses may result in a wide range of inflammatory disorders. Innate immune cells immediately respond to initiate the inflammatory responses to microbial infection and cellular injury, and the responses can be prolonged for duration of time. Sustained cytokine production by macrophages contributes to the prolonged inflammation in vivo. Our preliminary study shows that induction of cell surface 4-1BB ligand (4-1BBL) is essentially required for the sustained TNF production in macrophages. This signaling mechanism occurs sequentially; 4-1BBL is induced in TLR pathway-dependent manner at the initial phase and translocates to the cell surface to form a complex with TLRs at the later phase to activate downstream signaling. Inhibition of the later phase secondary signaling pathway resulted in the reduction of inflammatory responses, and this indicates that 4-1BBL signaling is the potential target of anti-inflammation treatment. However, there are still missing steps in the initial and secondary signaling pathways which control TNF production and its relevance in inflammatory disorder is unclear. We therefore hypothesized that 4-1BBL, expression of which is mediated by TLR-specific signaling pathways, induces a novel second signaling mechanism to sustain the inflammatory response. We propose following specific aims to test our hypothesis. In Aim 1, we will investigate the signaling mechanism of 4-1BBL-mediated TNF production focusing such as the involvement and interaction of signaling molecules in 4-1BBL-mediated secondary signaling pathway. In Aim 2, we will investigate the expression mechanism of 4-1BBL in TLR-mediated signaling pathway to define the specificity of 4-1BBL in inflammatory responses in TLR signaling. Aim 3 is focused on the suppression of inflammatory responses by blocking 4- 1BBL signaling by targeting the 4-1BBL-mediated signaling to reduce the sustained inflammatory response. The studies in this proposal will answer the fundamental question of how inflammation is regulated. The knowledge obtained from these studies will be extended to biological studies and will help to develop new strategies of novel anti-inflammatory therapeutics. PUBLIC HEALTH RELEVANCE: This project is aimed at understanding the molecular mechanism of sustained cytokine production in macrophages and its application to anti-inflammation treatment. We will determine the 4-1BBL-mediated signaling pathways underlying the signaling events that are essential for sustained cytokine production. The information obtained from this study will help to develop new strategies to treat inflammatory diseases.