Studies Of The Bioregulatory Aspects Of The Retinal Pigment Epithelial Cell

视网膜色素上皮（retinal pigment epithelial，RPE）细胞在维持神经视网膜的结构和生理完整性中起着基本作用。其结构和功能作用的改变可导致光感受器和视力的丧失。我们已经广泛地研究了RPE细胞作为眼后极内的重要免疫调节细胞。我们对RPE细胞的研究活动可以分为三类：正常细胞功能研究，细胞因子相互作用和感染过程。该项目集中于研究细胞因子与免疫系统细胞和眼部微环境细胞相互作用的方式。这些研究表明，甜菜碱介导的RPE细胞活化可能是眼免疫的基本组成部分，也是RPE细胞移植的重要方面。 在过去的一年中，我们研究了视网膜中免疫反应的调节。RPE细胞在免疫防御中起着关键作用，因为它协调先天免疫和适应性免疫。 然而，由于视网膜内不受控制的炎症反应本身可导致细胞损伤，因此需要向下调节力来限制免疫病理损伤。 这可能是AMD等疾病的重要因素。 我们假设由RPE细胞产生的IFN-β、IL-11和TGF-α是该限制力的关键组分。 我们的研究的目的是定义和阐明触发IL-11和IFN-β的因素;在人类RPE细胞的生产，并确定这些细胞因子发挥免疫调节的机制。 我们已经确定了IFN-β的免疫调节作用的三个不同方面。 (1)IFN-β抑制多种人类和小鼠细胞（包括：RPE、视网膜血管内皮细胞、神经胶质、神经母细胞瘤、巨噬细胞）中CXCL 9和ICAM-1的基因表达和蛋白质产生。 相反，CXCL 10和11不受抑制。(2)IFN-β治疗增加小鼠实验性脑型疟疾的存活率。 作用机制：脑组织中CXCL 9和ICAM-1基因表达下调，脑内皮细胞上CXCL 9表达下调，血脑屏障渗漏减少，T细胞向脑的迁移减少，脾脏T细胞上CXCR 3表达减少。 (3)IFN-b治疗抑制Th 1模型系统中的眼部炎症。 作用机制：降低Th 1细胞上CXCR 3的表达。 这些结果表明RPE细胞衍生的IFN-β抑制视网膜中CXCL 9和ICAM-1表达的关键作用，并表明这种抑制是保护视网膜免受过度炎症和损伤的免疫抑制机制。 在过去的一年中，我们还鉴定和表征了免疫抑制细胞因子IL-11的RPE细胞产生。 在用TGF-β、IL-1和TNF-α处理的人RPE细胞中，IL-11基因表达和蛋白质释放上调。 生产受到IFN-γ的下调。 正在进行研究以评估IL-11的免疫抑制作用。 因此，更好地了解IL-11和IFN-β的免疫调节作用可能会提供新的治疗方式和干预策略的见解。 此外，研究正在确定RPE免疫抑制功能的缺陷是否与视网膜疾病（例如AMD）中的慢性炎症相关。

The retinal pigment epithelial (RPE) cell plays a basic role in maintaining the structural and physiological integrity of the neural retina. Alterations in its structural and functional actions can result in loss of photoreceptors and vision. We have studied the RPE cell extensively as an important immunoregulatory cell within the posterior pole of the eye. Our research activities on RPE cells can be subdivided into three categories: normal cell function studies, cytokine interactions and infectious processes. This project has concentrated on studying the ways in which cytokines interact with cells of the immune system and with cells in the ocular microenvironment. These studies indicate that cytokine-mediated activation of RPE cells may be a basic component of ocular immunity and an important aspect of RPE cell transplantation. During the past year, we have studied the regulation of immune reactivity in the retina. The RPE cell plays a pivotal role in immune defense, since it orchestrates both innate and adaptive immunity. However, since an uncontrolled inflammatory response within the retina can itself lead to cellular damage, a down regulatory force is needed to limit immunopathologic damage. This may be an essential element in diseases such as AMD. We hypothesize that IFN-beta;, IL-11 and TGF-alpha; produced by the RPE cell are critical components of that limiting force. The aim of our studies was to define and elucidate the factors that trigger IL-11 and IFN-beta; production in human RPE cells and to identify mechanisms by which these cytokines exert immunoregulation. We have identified three different aspects of immunoregulatory actions of IFN-beta. (1) IFN-beta inhibits gene expression and protein production of CXCL9 and ICAM-1 in a variety of human and mouse cells (including: RPE, retinal vascular endothelial cells, glia, neuroblastoma, macrophage). In contrast, CXCL10 and 11 are not inhibited.(2) IFN-beta treatment increases survival in experimental cerebral malaria in mice. Mechanisms of action: down-regulation of CXCL9 and ICAM-1 gene expression in the brain, down-regulation of CXCL9 expression on brain endothelial cells, decrease leakage in BBB, decreased migration of T cells to the brain, decrease expression of CXCR3 on T cells in spleen. (3) IFN-b treatment inhibits ocular inflammation in Th1 model system. Mechanism of action: decreased expression of CXCR3 on Th1 cells. These results indicate a critical role for RPE-cell derived IFN-beta that inhibits CXCL9 and ICAM-1 expression in the retina and suggest that this inhibition is an immuno-suppressive mechanism that protects the retina from excessive inflammation and damage. During the past year we have also Identified and characterized RPE cell production of the immunosuppressive cytokine IL-11. IL-11 gene expression and protein release is up regulated in human RPE cells treated with TGF-beta;, IL-1 and TNF-alpha;. Production is down regulated by IFN-gamma. Studies are ongoing to evaluate immune suppressive actions of IL-11. Thus, a better understanding of the immunoregulatory actions of IL-11 and IFN-beta may provide insight into novel therapeutic modalities and interventive strategies. Moreover, studies are on going to determine whether defects in the RPE immune suppressive functions are associated with chronic inflammation in retinal diseases, such as, AMD.