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

描述(申请人提供)：炎症是一种有益的反应，可以限制细胞和器官的损害，保护身体免受感染或移除受损的组织，炎症反应调节的崩溃可能导致广泛的炎症性疾病。先天免疫细胞会立即对微生物感染和细胞损伤做出反应，这种反应可以延长一段时间。巨噬细胞持续产生细胞因子是体内炎症延长的原因之一。我们的初步研究表明，细胞表面4-1BB配体(4-1BBL)的诱导是巨噬细胞持续产生肿瘤坏死因子所必需的。这种信号机制是按顺序发生的；4-1BBL在起始阶段以TLR途径依赖的方式被诱导，并在后期移位到细胞表面，与TLRs形成复合体，激活下游信号。抑制晚期二级信号通路可减少炎症反应，提示4-1BBL信号通路是抗炎治疗的潜在靶点。然而，在控制肿瘤坏死因子产生的初始和次级信号通路中仍有缺失的步骤，其与炎症性疾病的相关性尚不清楚。因此，我们推测，4-1BBL的表达由TLR特异的信号通路介导，它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。在目标1中，我们将重点研究4-1BBL介导的肿瘤坏死因子产生的信号机制，如信号分子在4-1BBL介导的二级信号通路中的参与和相互作用。目的2研究4-1BBL在TLR介导的信号通路中的表达机制，以明确4-1BBL在TLR信号转导的炎症反应中的特异性。目的3通过靶向4-1BBL介导的信号转导来阻断4-1BBL信号通路，从而抑制炎症反应，从而减少持续的炎症反应。这项提案中的研究将回答如何调控炎症的根本问题。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.