The 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. Cytokines, such as interferon (IFN)-gamma and IL-2, are a group of specialized hormone-like proteins which exert profound influences on cellular development and on a variety of cellular functions. 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. Studies were initiated to evaluate the transcription factors in IFN-gamma activation of RPE cells. These studies revealed that IFN-gamma induced transcription factors IRF-1 and IRF-2 (interferon regulatory factors) in HRPE cells through the activation of STAT-1. Additional studies have concentrated on the interactions of infectious agents with HRPE cells and the subsequent activation of cytokine gene expression. Initial studies demonstrated that Toxoplasma gondii replication in HRPE cells was dramatically inhibited by the cytokine IFN-gamma. When T. gondii replicated in HRPE cells, the cells secreted the following cytokines, IL-1, IL-6, GM-CSF and the adhesion molecule, ICAM-1. Northern blot and RT-PCR analyses showed enhanced mRNA levels suggesting activation at transcriptional level. Since these induced cytokines and ICAM-1 are potent proinflammatory molecules, our data suggest that the infection of HRPE cells may significantly contribute to the inflammation associated with retinochoroiditis due to ocular toxoplasmosis.
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