Interferons enhance HLA-G mRNA and protein in transfected mouse fibroblasts

Chu, Wenjiang; Yang, Yaping; Geraghty, Daniel E.; Hunt, Joan S.

doi:10.1016/s0165-0378(98)00077-1

Cited by 46 publications

(30 citation statements)

References 35 publications

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“…The extent of up-regulation of HLA-G transcript levels we observed in IFN-␤-treated primary cells, cell lines, and trophoblast tissue was in agreement with the 2-2.5-fold enhancement reported previously and may not be attributed to increased stability of mRNA but rather to stimulation of the HLA-G transcription rate (35). Our results confirm that IFN-␤ is a potent inducer of HLA-G transcription, which may explain the effect observed at the surface of HLA-G-expressing cells, although a posttranscriptional effect of IFN-␤ on HLA-G enhancement cannot be excluded.…”

Section: Figsupporting

confidence: 92%

“…No adjacent cooperative sequence seems to be required for full induction by IFN-␤ through the functional ISRE within the HLA-G promoter, which identifies the particular nature of IFN-␤-mediated HLA-G induction. The level of IFN-␤-mediated induction of HLA-G surface antigens was quite well correlated to the level of HLA-G promoter transactivation through the Ϫ746 ISRE and was similar to that reported using a transfected HLA-G 6.0-kb fragment containing the 1.4-kb promoter fragment and 3Ј sequences (35). Nevertheless, we cannot exclude the presence of other functional IFN-responsive sites within the HLA-G gene.…”

Section: Figsupporting

confidence: 87%

“…HLA-G expression can be induced by IFN-␣ and IFN-␥ in transfected mouse fibroblasts (35). Whether the functional ISRE is able to mediate transcriptional activation of HLA-G upon both type I IFNs remains to be verified.…”

Section: Figmentioning

confidence: 99%

“…DISCUSSION A previous study reported the ability of IFN-␤ to enhance levels of HLA-G surface antigens, but these data remained preliminary because they were only reported on transfected mouse fibroblasts. Although IFN-␤ was identified as a potent inductor of HLA-G transcription in other cell types (33)(34)(35), the regulatory pathways yielding to this transactivation were not elucidated. Indeed, little is known about sequences and factors that participate in transactivation of the HLA-G promoter, in which most of the conserved regulatory DNA elements involved in the constitutive and cytokine-induced expression of the HLA class I genes are disrupted and nonfunctional.…”

Section: Figmentioning

confidence: 99%

“…HLA-G gene expression can be activated by interleukin 10 (31), glucocorticoids, or stress treatment (32) independently of classical HLA class I genes or by IFNs (33)(34)(35)(36), despite deleterious mutations within the HLA-G promoter of critical cis-acting regulatory elements involved in the constitutive and interferon-inducible transcription of HLA-class I genes (enhancer-A, ISRE, and site ␣) (37)(38)(39).…”

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confidence: 99%

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A Specific Interferon (IFN)-stimulated Response Element of the Distal HLA-G Promoter Binds IFN-regulatory Factor 1 and Mediates Enhancement of This Nonclassical Class I Gene by IFN-β

Lefebvre

Berrih‐Aknin

Adrián

et al. 2001

Journal of Biological Chemistry

106

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Section: Figsupporting

confidence: 92%

Section: Figsupporting

confidence: 87%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

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A Specific Interferon (IFN)-stimulated Response Element of the Distal HLA-G Promoter Binds IFN-regulatory Factor 1 and Mediates Enhancement of This Nonclassical Class I Gene by IFN-β

Lefebvre

Berrih‐Aknin

Adrián

et al. 2001

Journal of Biological Chemistry

106

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Soluble human leukocyte antigen-G serum level is elevated in melanoma patients and is further increased by interferon-? immunotherapy

Ugurel

Rebmann

Ferrone

et al. 2001

Cancer

157

124

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BACKGROUND The nonclassic human major histocompatibility complex class I antigens human leukocyte antigen (HLA)–G are proposed to protect tumor cells from natural killer cell lysis. In the current study, the authors measured soluble HLA‐G molecules (sHLA‐G) in serum from patients with malignant melanoma. METHODS Soluble HLA‐G was determined in serum samples of 190 melanoma patients with various stages of disease, with or without current therapy including interferon (IFN)–α and different cytostatics in comparison to 126 healthy controls by using a two‐step enzyme‐linked immunoadsorbent assay. RESULTS Serum sHLA‐G was significantly (P < 0.0005) elevated in melanoma patients (mean ± standard error of the mean [SEM] = 41.95 ± 2.15 ng/mL) compared with healthy controls (mean ± SEM = 22.92 ± 1.51 ng/mL). Univariate analysis revealed a correlation of sHLA‐G serum level with advanced stages of disease (P < 0.001) and tumor load (P < 0.05). Patients undergoing immunotherapy with IFN‐α (n = 31) showed an increased serum sHLA‐G (mean ± SEM = 62.05 ± 7.58 ng/mL; P < 0.0005), whereas other treatment regimens (n = 24) did not influence sHLA‐G serum concentrations. Multivariate analysis revealed treatment with IFN‐α as the only impact factor for elevated serum sHLA‐G, lacking any correlation with stage of disease or tumor burden. Furthermore, IFN‐α was found to upregulate HLA‐G cell surface expression on circulating monocytes. sHLA‐G serum level was not associated with recurrence free or overall survival. CONCLUSIONS This study shows increased sHLA‐G serum concentrations in melanoma patients and additional enhancement upon treatment with IFN‐α. The level of serum sHLA‐G, however, had no negative impact on patients' prognosis. Cancer 2001;92:369–76. © 2001 American Cancer Society.

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HLA-G gene activation in tumor cells involvescis-acting epigenetic changes

Mouillot¹,

Marcou²,

Rousseau³

et al. 2004

Int. J. Cancer

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The tissue distribution of HLA-G molecules is broader than originally reported in trophoblastic cells. On the basis of numerous studies, HLA-G is also expressed in malignant tumors and involved in tumor immune escape. The mechanisms of HLA-G gene regulation differ from those of classical HLA class I genes and involve epigenetic processes. Here, we provide additional evidence on the influence of DNA demethylation on HLA-G activation. We also analyze the 5 regulatory region of HLA-G in 2 cellular models, melanoma (FON, M8) and choriocarcinoma (JEG-3, JAR), either expressing HLA-G transcripts or not. The data strongly suggest that HLA-G is silenced as a result of CpG site hypermethylation within a 5 regulatory region encompassing 450 bp upstream of the start codon, whereas it is activated upon demethylation. This result correlates with the acetylation status of histones within this region and the putative locus control region located at -1.2 kb. cis-acting epigenetic changes and the fact that demethylating agents activate HLA-G expression at least 5 days following treatment should be taken into account in epigenetic cancer therapies.

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Interferons enhance HLA-G mRNA and protein in transfected mouse fibroblasts

Cited by 46 publications

References 35 publications

A Specific Interferon (IFN)-stimulated Response Element of the Distal HLA-G Promoter Binds IFN-regulatory Factor 1 and Mediates Enhancement of This Nonclassical Class I Gene by IFN-β

A Specific Interferon (IFN)-stimulated Response Element of the Distal HLA-G Promoter Binds IFN-regulatory Factor 1 and Mediates Enhancement of This Nonclassical Class I Gene by IFN-β

Soluble human leukocyte antigen-G serum level is elevated in melanoma patients and is further increased by interferon-? immunotherapy

HLA-G gene activation in tumor cells involvescis-acting epigenetic changes

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