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Epigenetic silencing of the CIITA gene and posttranscriptional regulation of class II MHC genes in ocular melanoma cells.
Invest Ophthalmol Vis Sci. 2004 Sep; 45(9):3185-95.IO

Abstract

PURPOSE

Primary uveal melanocytes and many ocular melanoma cells are resistant to interferon (IFN)-gamma-mediated induction of major histocompatibility complex (MHC) class II molecule expression. This suppression of class II MHC induction is considered to be one of the ways in which the eye is able to inhibit inflammatory responses. However, the mechanism(s) of this suppression is unknown. In this study, we have probed the molecular basis of this phenotype and report two distinct mechanisms underlying this phenotype.

METHODS

Primary ocular melanocytes and ocular melanoma cell lines (retaining this IFN-gamma-resistant class II MHC phenotype) were examined for the expression of class II MHC molecules on the cell surface by flow cytometry. Class II MHC gene expression was further examined using Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses.

RESULTS

The IFN-gamma signal-transduction pathway was found to be intact by electrophoretic mobility shift assay (EMSA) and transfection of reporter constructs. The lack of class II MHC gene expression appears to result from at least two mechanisms: (1) a specific inhibition of CIITA (class II transactivator) gene expression (reminiscent of trophoblasts), and (2) posttranscriptional regulation of class II MHC genes.

CONCLUSIONS

The inability of primary uveal melanocytes and ocular melanoma cells to express class II MHC molecules after treatment with IFN-gamma has been found to map to two distinct points in the class II MHC biosynthetic pathway. The predominant mechanism appears to involve the silencing of the endogenous gene encoding the class II transactivator (CIITA). Here, the blockade does not involve signal transduction from the IFN-gamma receptor, but rather involves a specific silencing of the CIITA gene. A second mechanism involves the posttranscriptional regulation of class II MHC genes.

Authors+Show Affiliations

Department of Immunology, University College London, University of London, Moorfields Eye Hospital, London, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15326139

Citation

Radosevich, Michael, et al. "Epigenetic Silencing of the CIITA Gene and Posttranscriptional Regulation of Class II MHC Genes in Ocular Melanoma Cells." Investigative Ophthalmology & Visual Science, vol. 45, no. 9, 2004, pp. 3185-95.
Radosevich M, Song Z, Gorga JC, et al. Epigenetic silencing of the CIITA gene and posttranscriptional regulation of class II MHC genes in ocular melanoma cells. Invest Ophthalmol Vis Sci. 2004;45(9):3185-95.
Radosevich, M., Song, Z., Gorga, J. C., Ksander, B., & Ono, S. J. (2004). Epigenetic silencing of the CIITA gene and posttranscriptional regulation of class II MHC genes in ocular melanoma cells. Investigative Ophthalmology & Visual Science, 45(9), 3185-95.
Radosevich M, et al. Epigenetic Silencing of the CIITA Gene and Posttranscriptional Regulation of Class II MHC Genes in Ocular Melanoma Cells. Invest Ophthalmol Vis Sci. 2004;45(9):3185-95. PubMed PMID: 15326139.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epigenetic silencing of the CIITA gene and posttranscriptional regulation of class II MHC genes in ocular melanoma cells. AU - Radosevich,Michael, AU - Song,Zhimin, AU - Gorga,Joan C, AU - Ksander,Bruce, AU - Ono,Santa Jeremy, PY - 2004/8/25/pubmed PY - 2004/10/8/medline PY - 2004/8/25/entrez SP - 3185 EP - 95 JF - Investigative ophthalmology & visual science JO - Invest Ophthalmol Vis Sci VL - 45 IS - 9 N2 - PURPOSE: Primary uveal melanocytes and many ocular melanoma cells are resistant to interferon (IFN)-gamma-mediated induction of major histocompatibility complex (MHC) class II molecule expression. This suppression of class II MHC induction is considered to be one of the ways in which the eye is able to inhibit inflammatory responses. However, the mechanism(s) of this suppression is unknown. In this study, we have probed the molecular basis of this phenotype and report two distinct mechanisms underlying this phenotype. METHODS: Primary ocular melanocytes and ocular melanoma cell lines (retaining this IFN-gamma-resistant class II MHC phenotype) were examined for the expression of class II MHC molecules on the cell surface by flow cytometry. Class II MHC gene expression was further examined using Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses. RESULTS: The IFN-gamma signal-transduction pathway was found to be intact by electrophoretic mobility shift assay (EMSA) and transfection of reporter constructs. The lack of class II MHC gene expression appears to result from at least two mechanisms: (1) a specific inhibition of CIITA (class II transactivator) gene expression (reminiscent of trophoblasts), and (2) posttranscriptional regulation of class II MHC genes. CONCLUSIONS: The inability of primary uveal melanocytes and ocular melanoma cells to express class II MHC molecules after treatment with IFN-gamma has been found to map to two distinct points in the class II MHC biosynthetic pathway. The predominant mechanism appears to involve the silencing of the endogenous gene encoding the class II transactivator (CIITA). Here, the blockade does not involve signal transduction from the IFN-gamma receptor, but rather involves a specific silencing of the CIITA gene. A second mechanism involves the posttranscriptional regulation of class II MHC genes. SN - 0146-0404 UR - https://www.unboundmedicine.com/medline/citation/15326139/Epigenetic_silencing_of_the_CIITA_gene_and_posttranscriptional_regulation_of_class_II_MHC_genes_in_ocular_melanoma_cells_ L2 - https://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.04-0111 DB - PRIME DP - Unbound Medicine ER -