Studies Of The Bioregulatory Aspects Of The Retinal Pigment Epithelial Cell

视网膜色素上皮(RPE)细胞在维持神经视网膜的结构和生理完整性方面起着基础性作用。其结构和功能的改变会导致光感受器和视力的丧失。我们对RPE细胞作为眼后极重要的免疫调节细胞进行了广泛的研究。我们对RPE细胞的研究活动可分为三类：正常细胞功能研究、细胞因子相互作用研究和感染过程研究。该项目致力于研究细胞因子与免疫系统的细胞以及眼部微环境中的细胞相互作用的方式。这些研究表明，细胞因子介导的RPE细胞活化可能是眼免疫的一个基本组成部分，也是RPE细胞移植的一个重要方面。 在过去的一年里，我们研究了视网膜免疫反应的调节。RPE细胞在免疫防御中起着关键作用，因为它既协调先天免疫又协调获得性免疫。然而，由于视网膜内不受控制的炎症反应本身会导致细胞损伤，因此需要一种向下调节的力量来限制免疫病理损伤。这可能是AMD等疾病的一个重要因素。我们假设RPE细胞产生的干扰素-β、IL-11和转化生长因子-α是该限制力的关键成分。本研究的目的是明确和阐明在人RPE细胞中产生IL-11和干扰素-β的因素，并确定这些细胞因子发挥免疫调节作用的机制。 我们已经确定了干扰素-β免疫调节作用的三个不同方面。(1)干扰素-β抑制多种人和小鼠细胞(包括RPE、视网膜血管内皮细胞、神经胶质细胞、神经母细胞瘤、巨噬细胞)中CXCL9和ICAM-1的基因表达和蛋白产生。相反，CXCL10和CXCL11没有被抑制。(2)干扰素-β治疗提高了实验性脑疟疾小鼠的存活率。(3)干扰素-b治疗对Th1模型眼部炎症有抑制作用。作用机制：减少Th1细胞表面CXCR3的表达。这些结果表明，RPE细胞来源的干扰素-β在抑制视网膜中CXCL9和ICAM-1的表达方面发挥了关键作用，并表明这种抑制是一种免疫抑制机制，可以保护视网膜免受过度炎症和损伤。在过去的一年里，我们还鉴定并鉴定了RPE细胞产生免疫抑制细胞因子IL-11的特性。人RPE细胞经转化生长因子-β_1、IL-1和肿瘤坏死因子-α处理后，IL-11基因表达和蛋白释放上调。干扰素-γ下调了细胞的产量。评估IL-11的免疫抑制作用的研究正在进行中。因此，更好地了解IL-11和干扰素-β的免疫调节作用可能会为新的治疗方式和干预策略提供洞察。此外，正在进行研究，以确定RPE免疫抑制功能缺陷是否与视网膜疾病(如AMD)的慢性炎症有关。

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.