Oncostatin M and Leukemia Inhibitory Factor Biology

对组织损伤和感染的急性期应答的开始和进展由白细胞介素-6（IL-6）型细胞因子的成员控制。而IL-6介导的全身反应，制瘤素M（OSM）和白血病抑制因子（LIF）作为局部激活过程的关键介质。OSM诱导成纤维细胞/基质细胞中IL-6和细胞外基质蛋白的表达，而在神经元和肌肉损伤部位，LIF促进再生。所有IL-6型细胞因子诱导肝脏中急性期反应的组分，然而，肝细胞和成纤维细胞通过基因调控和生长的差异模式对IL-6、OSM和LIF作出反应。通过检验这一假设，即精氨酸特异性的行动是由构成个别受体复合物的亚基的胞质结构域决定的，我们已经分配了亚基特异性的信号传导功能，OSM受体β和LIF受体α是不同于常见的信号转导亚基gp 130。由于建立OSM和LIF特异性反应的确切机制尚不清楚，本项目的目标1是确定OSMR β和LIFR α胞质结构域内的功能基序，这些功能基序决定了肝和成纤维细胞模型中的特异性反应。本提案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IL- 6型细胞因子合作介导LIF和OSM反应性的差异性和细胞类型特异性降低。我们的工作表明，LIFR功能的优先衰减的LIFR α降解的一种新的机制，在一定程度上，依赖于丝氨酸激酶基序在胞质结构域的LIFR α。将在肝和成纤维细胞模型中定义LIFR α和OSMR β转换的生化过程以及由胰岛素和生长因子激活的触发LIFR α反式降解的途径。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期间操纵有益的IL-6细胞因子效应的治疗。

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.