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Y. Chen, J. Foon, J. Cai, P. Sternberg; Immunosuppressor FK506 Enhances IFN-Gamma-Stimulated Complement Factor H Expression in the RPE. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5165.
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Genetic variations of the complement factor H (CFH) gene have been associated with age-related macular degeneration (AMD). Decreased expression or activity of CFH may increase the risk of developing AMD. In this study, we explored the regulation of CFH expression by FK506, an immunosuppressive drug, in cultured human RPE cells.
ARPE-19 cells were exposed to different concentrations of IFN-gamma in the absence or presence of FK506. The mRNA and protein levels of CFH were determined by real-time RT-PCR and Western blot analysis, respectively. STAT1 activity was measured by a reporter assay after transient transfection. AG490 and pyridone 6 were used to inhibit JAK/STAT pathway in the RPE.
IFN-gamma stimulated CFH expression in a STAT1-dependent manner in the RPE. Co-treatment with FK506 enhanced IFN-gamma-stimulated CFH expression at both mRNA and protein levels. The effects of FK506 were selective, as it did not affect other IFN-gamma-regulated genes, including ICAM 1 and IRF. However, FK506 did not alter the transactivation function of STAT1 after IFN-gamma treatment.
FK506 is capable of regulating interferon stimulated-CFH production in the RPE. Immunosuppressive agents functioning through the FKBP/Calcineurin/NFAT pathway may have potential applications in regulating inflammatory responses associated with AMD.
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