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. Platelet derived growth factors (PDGF) are known to be associated with retinal proliferative and angiogenic disorders such as PVR and ARMD. PDGF promotes proliferation and migration of fibroblasts, pericytes and smooth muscle cells. Our studies indicated that TGF-b is a potent inducer of PDGF-AA and PDGF-AB in RPE cells while choroidal fibroblasts (CHF) do not produce PDGF. Receptors for PDGF are highly expressed on CHF but not on RPE. Human recombinant PDGF-isoforms (AA, AB, BB) significantly enhanced CHF proliferation, elongation and migration. In contrast no significant effects on RPE proliferation and migration were observed. These results show that PDGF secreted by RPE cells (stimulated by TGF-b) act on nearby connective tissue cells (fibroblasts) and possibly on vascular pericytes and smooth muscle cells. Consequent promotion of proliferation and migration of these target cells results in the pathogenesis of PVR and CNV in ARMD. Regulation of the expression of PDGF in RPE by TGF-b strongly suggests an important role for TGF-b in neovascularization associated with retinal disorders such as PVR and ARMD. Our previous and ongoing studies have shown a prominent role for TGF-b in many of the retinal diseases such as ARMD, PVR, and diabetic retinopathy as well as in inflammatory diseases. 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-g, which enhanced TGF-b1 but inhibited TGF-b2 production. Interestingly, other inflammatory mediators such as tumor necrosis factor-a 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. These 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.
Showing the most recent 10 out of 15 publications
