ROLE OF RETINAL PIGMENT EPITHELIUM IN RETINAL DISORDERS

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Human retinal pigment epithelial (HRPE) cell cultures were used as a model to investigate the various roles of HRPE in the pathophysiology of retinal disorders. We have recently reported that HRPE cells upregulate mRNA levels and secrete significant quantities of interleukin (IL) -6, intercellular adhesion molecule-1 (ICAM-1), granulocyte macrophage colony stimulating factor (GMCSF) and nitric oxide in response to the stimulation by inflammatory mediators interferon (IFN) gamma, IL-1 and tumor necrosis factor (TNF) -alpha. Signaling pathways of IFN-gamma in HRPE cells were evaluated to delineate the mechanisms of IFN-gamma action. Transcription factors IRF-1 and IRF-2 (interferon regulatory factors), but not ICSBP (interferon consensus sequence binding protein), were induced by IFN-gamma in HRPE cells. Electrophoretic mobility shift and supershift assays revealed that activation of IRF genes is mediated by STAT-1, a member of signal transducers and activators of transcription. Inflammation associated with retinochoroiditis due to ocular toxoplasmosis (OT) is one of the common causes of uveitis. In immunocompromised individuals such as AIDS patients and transplant recipients, OT may result in loss of vision. We have previously shown that Toxoplasma gondii (TG) can replicate in HRPE cells and the inhibition of replication by interferons. We have conducted studies to investigate the responses of HRPE cells in cytokine production during TG invasion and intracellular replication. TG infection of HRPE cells resulted in 5 to 20 fold increase in the secretion of IL-1, IL-6, GMCSF as well as ICAM-1. Northern blot and RT-PCR analyses indicated enhanced mRNA levels suggesting activation at transcriptional stage. However, secretion of IL-4, IL-10, IL-12, IL-15 or nitric oxide was not observed. The secretion of these cytokines by HRPE cells during TG infection suggests that cytokines play a critical role in the pathogenesis of TG induced retinochoroiditis.