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M.D. Radosevich, M.J. Jager, S.J. Ono; Inhibition of MHC Class II Gene Expression in Ocular Melanoma Cells Due to Methylation of the CIITA Gene or an Upstream Activator . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2812.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Most cells with an intact interferon (IFN)–gamma receptor and signalling pathway are able to express MHC class II molecules when treated with cytokines such as IFN–gamma. Primary uveal melanocytes and many ocular melanoma cells are resistant to interferon–gamma mediated induction of class II MHC genes. This suppression of MHC class II induction is considered to be one of the several ways in which the eye is able to inhibit inflammatory responses. We have previously demonstrated that the inability of ocular melanoma cells to express MHC class II molecules after treatment with IFN–gamma maps to two distinct points in the class II MHC biosynthetic pathway: the silencing of the endogenous gene encoding the class II transactivator (CIITA) and a mechanism that involves the posttranscriptional regulation of class II MHC genes. In this report we determine the mechanism of silencing the endogenous CIITA gene. Methods: Ocular melanoma cells were studied with demethylating agents, reverse transcriptase–polymerase chain reaction (RT–PCR) analyses, flow cytometry, and Southern blot analyses. Results: We have determined that methylation is responsible for the inhibition of class II inducibility in representative ocular melanoma cells. We also show that the precise site of methylation mediated silencing of the CIITA gene is unique from that in human trophoblast cells which are present at another site of immune privilege. Conclusions: A strong inflammatory reaction within the eye would be detrimental to sight and the inhibition of class II MHC expression may represent one of the several ways in which the eye can maintain an immune privileged status. We have demonstrated that methylation of either the CIITA gene or an upstream activator is responsible for the inhibition of class II MHC expression in ocular melanoma cells.
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