The role of the Interleukin-6 receptor in liver damage and regeneration

Interleukin-6受体在肝损伤和再生中的作用

• 批准号: 446322183
• 负责人: Professor Dr. Jürgen Scheller
• 金额: --
• 依托单位: Institut für Biochemie und Molekularbiologie II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/446322183?language=en
• 关键词: role; Interleukin; receptor; liver; damage

The interference of immune response and liver damage/-regeneration is controlled by cytokines of the Interleukin (IL-)6 family. Recently, we have demonstrated that mainly IL-6 trans-signalling directly and indirectly promotes hepatocyte proliferation and is sufficient for liver regeneration following partial hepatectomy (PHX). In addition to IL-6, other IL-6 type cytokines including IL-11, OSM and LIF affect liver regeneration. In this research project, we will unravel the cell-type specific contribution of IL-6 pathways during liver regeneration following PHX using a variety of transgenic mouse models. First of all, we will analyze which cell types of the liver express IL-6 type cytokines and their receptors during PHX including IL-6, IL-11, OSM, and LIF. Since IL-6R deficient mice have a disfunctional liver regeneration, the potential to rescue this phenotype by these cytokines following PHX will be determined. Moreover, we will define the target cells of IL-6 signalling during liver regeneration following PHX. To this end, liver regeneration after PHX will be monitored in mice displaying a tissue specific conditional IL-6R deficiency in hepatocytes, hepatic stellate cells, macrophages, or T cells. Vice versa gain-of-function will be studied using tissue specific expression of L-gp130 and GVHH-gp130. L-gp130 is a synthetic ligand-independent, constitutive active gp130 receptor variant, which is able to initiate and maintain cell-autonomous IL-6 signal transduction. GVHH-gp130 is a switchable synthetic gp130 cytokine receptor, which can be activated by dimeric GFP (green fluorescent protein)-ligands. For GVHH-gp130, we will induce synthetic IL-6 signalling by injection of recombinant homodimeric GFP fusion proteins, to determine the optimal regenerative time window of IL-6 signalling. Expression of L-gp130 and GVHH-gp130 in transgenic mice will be initiated after crossing to Cre-recombinase expressing mice, which facilitates tissue specific expression in hepatocytes, hepatic stellate cells, macrophages, or T cells. These mice will be crossed onto the IL-6R deficient background to disable endogenous, natural IL-6 signalling before monitoring the liver regeneration following PHX. This analysis will allow the characterization of IL-6-dependent, regeneration competent cell types of the liver during the damage and regeneration phases. The project aims to elucidate the currently unknown cell-type specific function of IL-6 in liver regeneration following PHX using/employing common loss-of-function and novel gain-of-function transgenic mouse models.

免疫应答和肝损伤/再生的干扰由白细胞介素（IL-）6家族的细胞因子控制。最近，我们已经证明，主要是IL-6 trans-signaling直接和间接促进肝细胞增殖，是足够的肝再生后部分肝切除术（PHX）。除IL-6外，其他IL-6型细胞因子包括IL-11、OSM和LIF也影响肝再生。 在这个研究项目中，我们将使用各种转基因小鼠模型来阐明PHX后肝再生过程中IL-6通路的细胞类型特异性贡献。首先，我们将分析在PHX过程中哪些肝脏细胞类型表达IL-6型细胞因子及其受体，包括IL-6，IL-11，OSM和LIF。 由于IL-6 R缺陷型小鼠具有功能障碍性肝再生，因此将确定PHX后这些细胞因子拯救该表型的潜力。此外，我们将确定PHX后肝再生过程中IL-6信号传导的靶细胞。为此，将在肝细胞、肝星状细胞、巨噬细胞或T细胞中显示组织特异性条件性IL-6 R缺乏的小鼠中监测PHX后的肝再生。反之亦然，将使用L-gp 130和GVHH-gp 130的组织特异性表达来研究功能获得。L-gp 130是一种合成的配体非依赖性、组成型活性gp 130受体变体，其能够启动和维持细胞自主性IL-6信号转导。GVHH-gp 130是一种可转换的合成gp 130细胞因子受体，其可被二聚体GFP（绿色荧光蛋白）-配体激活。对于GVHH-gp 130，我们将通过注射重组同源二聚体GFP融合蛋白来诱导合成的IL-6信号传导，以确定IL-6信号传导的最佳再生时间窗。转基因小鼠中L-gp 130和GVHH-gp 130的表达将在与表达Cre重组酶的小鼠杂交后开始，这有助于肝细胞、肝星状细胞、巨噬细胞或T细胞中的组织特异性表达。将这些小鼠杂交到IL-6 R缺陷背景中，以在监测PHX后的肝再生之前禁用内源性天然IL-6信号传导。该分析将允许在损伤和再生阶段期间表征肝脏的IL-6依赖性再生能力细胞类型。该项目旨在阐明目前未知的细胞类型特异性功能的IL-6在PHX后使用/采用常见的功能丧失和新的功能获得转基因小鼠模型的肝再生。