Role of Retinal Pigment Epithelium In Retinal Disorders

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Retinal pigment epithelium (RPE), a single layer of cells present between the retina and choroid in the eye, is vital for the normal functioning of the retina. Many of the inflammatory, infectious and other diseases of the retina are associated with the degeneration and /or dysfunction of the RPE. We have developed a human RPE cell culture system and have used this as a model to investigate the various roles of RPE in the pathophysiology of retinal disorders. We focused our attention on transforming Growth factor-beta (TGF-b), since TGF-b is involved in retinal disorders of proliferative, inflammatory and infectious etiology. Retinal and Choroidal neovascularization (CNV), observed during age related macular degeneration (ARMD) and proliferative vitreoretinopathy (PVR) associated with retinal detachments, are the leading causes of visual impairment. Elevated expression of TGF-b in vitreous, retina and RPE has been closely correlated with the retinal fibrosis and CNV. However, the sources and production of TGF-b by retinal resident cells were not clearly known. We have examined the role of various cytokines and other mediators in the regulation of the expression of TGF-b by RPE. Our results demonstrated a differential role for interferon (IFN)-g, which enhanced TGF-b1 but inhibited TGF-b2 production. Interestingly, other inflammatory mediators such as tumor necrosis factor (TNF)-alpha and interleukin-1 enhanced the secretion of both TGF-b1 and TGF-b2. These observations were corroborated by mRNA analyses by Real-time and conventional RT-PCR methods. The contrasting effects of IFN-g on TGF-b1 and TGF-b2 sheds new light on the possible differential actions of TGF-b1 and TGF-b2 in the pathophysiology of retinal diseases. Further studies are in progress to evaluate the potential role of TGF-b1 and TGF-b2 and their receptors in the retinal diseases. We evaluated the effects of TGF-b on human RPE cells by microarray analyses by using GeneChip (Human Genome U133 plus array,Affymetrix). This will provide genome-wide changes in the expresssion of most of the characterized human genes. TGF-b significantly enhanced the expressionn of many of the extracellular matrix proteins(ECM)such as collagens, fibronectin, thrombospondin and chondritin sulfate proteoglycans. TGF-b treatment also enhanced the expression of vascular endothelial growth factors, connective tissue growth factor and platelet derived growth factors. ECM and growth factors are assocciated with many of the blinding retinal disorders like age related macular degeneration, retinal detachments and proliferative vitreoretinopathy. We are in the process of validation and quantitation of these results by Real Time PCR analyses. The role of ECM, growth factors and TGF-b in retinal diseases is the subject of our ongoing and future studies.