IL17 RECEPTOR VARIANTS IN INTESTINAL EPITHELIAL CELLS

白细胞介素-17是最近发现的一种细胞因子，由活化的淋巴细胞分泌。IL-17可能参与炎症过程，因为它能够激活NF-kappaB，随后刺激炎症细胞因子的表达。我们从人小肠cDNA文库中克隆了人IL-17受体。在这项工作中，我们观察到人类IL-17受体的四种变体，包括一种潜在的可溶性IL-17受体。初步实验表明，啮齿动物和人类肠上皮细胞表达功能性IL-17受体。肠上皮细胞对IL-17刺激的生物学反应包括调控上皮间电阻和TRAF6依赖性NF-kappaB的激活，随后诱导趋化因子mRNA的表达。然而，在IL-17结合时与IL-17受体相互作用的信号转导介质尚不清楚。此外，小鼠和人类IL-17受体的细胞质区和信号换能器的功能显著基序尚未确定。总的假设是，人类IL-17受体的变异可能调节肠上皮细胞中不同的细胞反应。本研究的总体目标是表征人IL-17受体的生物学功能以及介导这些功能的信号转导和转录激活事件。本实验的目的是进一步了解IL-17配体受体系统的信号转导及其在调节人肠上皮细胞功能中的作用。

Interleukin-17 is a recently identified cytokine, which is secreted by activated lymphocytes. IL-17 may be involved in inflammatory processes because it is able to activate NF-kappaB with the subsequent stimulation of inflammatory cytokine expression. We have cloned the human IL-17 receptor from a human small intestinal cDNA library. In this effort we observed four variants of the human IL-17 receptor including a potential soluble IL-17 receptor. Initial experiments demonstrate that rodent and human intestinal epithelial cells express functional IL-17 receptors. The biological responses of intestinal epithelial cells to IL-17 stimulation include the regulation of transepithelial electrical resistance and the TRAF6 dependent activation of NF-kappaB with the subsequent induction of chemokine mRNA expression. However, the signal transduction mediators interacting with the IL-17 receptor upon IL-17 binding are unknown. Furthermore, the functionally significant motifs in the cytoplasmic region and the signal transducer of the mouse and human IL-17 receptors have not been identified. The overall hypothesis is that the variants of the human IL-17 receptor may regulate separate and distinct cellular responses in intestinal epithelial cells. The overall goal of this study is to characterize the biologic function of the human IL-17 receptor and the signal transduction and transcriptional activation events mediating these functions. The purpose of our experiments will be to provide an increased understanding of the signal transduction of IL-17 ligand-receptor system and its role in regulation of human intestinal epithelial cell function.