Oncostatin M and Leukemia Inhibitory Factor Biology

对组织损伤和感染的急性时相反应的启动和进展由白细胞介素6(IL-6)类细胞因子的成员控制。IL-6介导全身反应，而抑瘤素M(OSM)和白血病抑制因子(LIF)则是局部激活过程的关键介质。OSM诱导成纤维细胞/基质细胞表达IL-6和细胞外基质蛋白，而在神经元和肌肉损伤部位，LIF促进再生。所有IL-6型细胞因子都能诱导肝脏的急性期反应，而肝脏和成纤维细胞对IL-6、OSM和LIF的反应是通过不同的基因调控和生长模式来实现的。通过检验细胞因子的特异性作用由组成单个受体复合体的亚基的细胞质结构域决定的假设，我们将不同于共同信号转导亚单位gp130的亚基特异性信号功能分配给OSM受体β和LIF受体α。由于建立OSM和LIF特异性反应的确切机制尚不清楚，本项目目标1的目标是在OSMRbeta和LIFRpha的细胞质结构域中确定决定肝脏和成纤维细胞模型中特异性反应的功能基序。这项建议的第二个目的是了解细胞如何整合多种细胞因子和生长因子的信号，这些细胞因子和生长因子与1L-6型细胞因子协同作用，介导LIF和OSM反应性的差异和细胞类型特异性降低。我们的工作表明，LIFR功能的优先衰减是通过一种新的LIFRα降解机制，这种机制部分依赖于LIFR胞浆结构域中的丝氨酸激酶基序。肝脏和成纤维细胞模型将定义LIFRpha和OSMRβ转化的生化过程以及由胰岛素和生长因子激活的触发反式LIFRpha降解的途径。了解IL-6型细胞因子受体活性的细胞类型特异性调节将有助于设计在炎症和组织修复过程中操纵有益的IL-6细胞因子效应的治疗方法。

Initiation and progression of acute phase response to tissue injury and infection are controlled by members of the interleukin-6 (IL-6) type cytokines. Whereas IL-6 mediates systemic responses, oncostatin M (OSM) and leukemia inhibitory factor (LIF) act as critical mediators of local activation processes. OSM induces the expression of IL-6 and extracellular matrix proteins in fibroblast/stromal cells, whereas at sites of neuronal and muscle damage, LIF promotes regeneration. All IL-6- type cytokines induce components of the acute phase reaction in liver, however, hepatic and fibroblastic cells respond to IL-6, OSM and LIF by differential patterns of gene regulation and growth. By testing the hypothesis that cytokine-specific action is determined by the cytoplasmic domains of the subunits constituting the individual receptor complexes, we have assigned subunit-specific signaling functions to OSM receptor beta and LIF receptor alpha that are distinct from that of the common signal transducing subunit gp130. Since the precise mechanisms by which OSM- and LIF-specific responses are established are unknown, the goal of Aim 1 of this project is to identify functional motifs within the cytoplasmic domains of the OSMRbeta and LIFRalpha that determine specific responses in hepatic and fibroblastic cell models. The second aim of this proposal is to understand how the cell integrates the signals of multiple cytokines and growth factors that cooperate with 1L- 6-type cytokines in mediating differential and cell type specific reduction in LIF and OSM responsiveness. Our work has suggested a preferential attenuation of the LIFR functions by a novel mechanism of LIFRalpha degradation that, in part, depends on a serine kinase motif in the cytoplasmic domain of LIFRalpha. The biochemical processes of LIFRalpha and OSMRbeta turnover and the pathways activated by insulin and growth factor trigger LIFRalpha degradation in trans will be defined in the hepatic and fibroblastic cell models. Understanding the cell type-specific regulation of IL-6-type cytokine receptor activities will assist in designing treatments that will manipulate beneficial IL-6 cytokine effects during inflammation and tissue repair.