Joint Effects of Epstein-Barr Virus and Polymorphisms in Interleukin-10 and Interferon-γ on Breast Cancer Risk

Abstract Interleukin-12 (IL-12) production by human monocytes is stringently regulated through the inducibility of both subunits, p35 and p40, and expression of p35 mRNA is the limiting factor for the secretion of the bioactive IL-12 p70 heterodimer. Optimal induction of p35 mRNA requires priming of the monocytes by interferon-γ (IFN-γ), followed by brief exposure to lipopolysaccharide or other bacterial products. To investigate control of p35 gene expression, we isolated genomic clones containing the human p35 gene and determined the 5′ end of the mRNA expressed in monocytes. We discovered that a unique p35 transcript is induced in monocytes that begins downstream of a consensus TATA box that lies within the 5′ end of the cDNA originally cloned from Epstein-Barr virus (EBV)-transformed B cells. Analysis of p35 mRNA by Northern blotting showed that the message from monocytes is approximately 200 bases shorter than message derived from the EBV-transformed B-cell line VDS. The initiation sites downstream from the TATA box were confirmed by RNase protection and 5′ RACE. The data indicate that p35 transcription can initiate from different sites depending on the cell type and that the shorter inducible transcript in monocytes is the one that accumulates after stimulation. Protein translation of these two forms may result in proteins of different sizes with potential implications for the regulation of IL-12 secretion and function.

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Breast Cancer as an Epstein-Barr Virus (EBV)-Associated Malignancy

Breast Cancer - From Biology to Medicine ◽

10.5772/66988 ◽

2017 ◽

Author(s):

Ghimja Fessahaye ◽

Muntaser E. Ibrahim

Keyword(s):

Breast Cancer ◽

Epstein Barr Virus ◽

Barr Virus ◽

Associated Malignancy ◽

Epstein Barr

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Interferon-γ Prevents Apoptosis in Epstein-Barr Virus-Infected Natural Killer Cell Leukemia in an Autocrine Fashion

Blood ◽

10.1182/blood.v93.10.3494.410k14_3494_3504 ◽

1999 ◽

Vol 93 (10) ◽

pp. 3494-3504 ◽

Cited By ~ 16

Author(s):

Shin-ichi Mizuno ◽

Koichi Akashi ◽

Koichi Ohshima ◽

Hiromi Iwasaki ◽

Toshihiro Miyamoto ◽

...

Keyword(s):

Natural Killer Cell ◽

Cell Survival ◽

Epstein Barr Virus ◽

Killer Cell ◽

Interferon Γ ◽

Leukemia Cells ◽

Cell Leukemia ◽

Barr Virus ◽

Ifn Γ ◽

Epstein Barr

The significant function of cytokines includes maintenance of cell survival as well as induction of cell differentiation and/or proliferation. We demonstrate here that interferon-γ (IFN-γ) plays a role for progression of Epstein-Barr virus (EBV)-infected natural killer cell leukemia (NK leukemia) through maintaining cell survival. NK leukemia cells obtained from 7 patients had clonal episomal forms of EBV, indicating that the leukemic cells were of clonal origin. Although normal NK cells constitutively expressed Bcl-2, the EBV-infected NK leukemia cells lacked endogenous Bcl-2 expression and were hypersensitive to apoptosis in vitro. The addition of IFN-γ to the culture significantly inhibited their spontaneous apoptosis without inducing cell proliferation or upregulation of Bcl-2. The NK leukemia cells constitutively secreted IFN-γ, and the patients’ sera contained a high concentration of IFN-γ, levels that were high enough to prevent NK leukemia cells from apoptosis. Bcl-XL was not involved in the IFN-γ–induced NK leukemia cell survival. These data suggest that the acquisition of IFN-γ–mediated autocrine survival signals, other than Bcl-2 or BCL-XL, might be important for the development of EBV-infected NK leukemia.

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