scholarly journals Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon-γ–mediated pathways

2007 ◽  
Vol 204 (1) ◽  
pp. 141-152 ◽  
Author(s):  
Jianguo Liu ◽  
Xiuqin Guan ◽  
Xiaojing Ma
Keyword(s):  
Transcription Initiation ◽  
Gene Promoter ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Dependent Manner ◽  
Barr Virus ◽  
Ifn Γ ◽  
Epstein Barr ◽  
Activated Monocytes ◽  
Myeloid Differentiation Factor

Interleukin (IL)-27 is the newest member of the IL-12 family of heterodimeric cytokines composed of the Epstein-Barr virus–induced gene 3 and p28 chains. IL-27 not only plays an important role in the regulation of differentiation of naive T helper cells but also possesses antiinflammatory properties. IL-27 is an early product of activated monocytes/macrophages and dendritic cells. However, the mechanisms whereby inflammatory signals stimulate IL-27 production have not been explored. In this study, we investigated the transcriptional regulation of the mouse IL-27 p28 gene in macrophages in response to lipopolysaccharide (LPS) and interferon (IFN)-γ. We found that LPS-stimulated p28 production was completely dependent on the Toll-like receptor 4/myeloid differentiation factor 88 (MyD88)–mediated pathway but only partially dependent on nuclear factor κB c-Rel. IFN-γ–induced p28 production/secretion was also partially dependent on MyD88 but independent of c-Rel. We then cloned the mouse p28 gene promoter and mapped its multiple transcription initiation sites. Furthermore, we identified critical promoter elements that mediate the inductive effects of LPS and IFN-γ, separately and synergistically, on p28 gene transcription in a c-Rel– and interferon regulatory factor 1–dependent manner, respectively.

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

Blood ◽  
1999 ◽  
Vol 93 (10) ◽  
pp. 3494-3504 ◽  
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.

scholarly journals Cytokine induction after Epstein-Barr virus infection of peripheral T-lymphocytes in vitro

2010 ◽  
Vol 4 (1) ◽  
pp. 69-77
Author(s):  
Putrada Ninla-aesong ◽  
Jintana Pradutkanchana ◽  
Kusumarn Noipha ◽  
Winyou Mitarnun
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interferon Γ ◽  
Cell Infection ◽  
Barr Virus ◽  
Cytokine Induction ◽  
Tnf Α ◽  
Ifn Γ ◽  
Epstein Barr

Abstract Background: Although the presence of Epstein-Barr virus (EBV) in different T-cell malignancies has been widely reported, there is very few data available for EBV infection of normal T cells. This leads to the lack of knowledge on the early events after T cell infection. Objective: Investigate the early events occurring after normal human peripheral T-cells are infected with EBV in vitro. Methods: T-cells were treated with EBV in vitro. The expression of tumor necrosis factor- α (TNF-α) mRNA were determined using reverse-transcription (RT)-PCR, and the level of TNF-α and interferon- γ (IFN-γ) in the culture supernatant were measured using ELISA. The effect of virus inactivation on cytokine induction from T-cells was also determined. Results: At the beginning of T cell infection by EBV, the expression of several lytic EBV transcripts (BALF5, BcLF1, and BLLF1) were observed using RT-PCR. This indicated the susceptibility of in vitro EBV infection and the entering lytic cycle of EBV-infected T-cells. The interactions of EBV with T-cells lead to induction of inflammatory cytokines, tumour necrosis factor- α (TNF-α) and interferon- γ (IFN-γ), production from the T-cells. Inactivation of the virus by UV irradiation eliminated the TNF-α and IFN-γ induction by EBV, suggesting the involvement in the expression of viral gene(s). Conclusion: This in vitro analysis demonstrated the cytokine induction by EBV after primary infection of T-cells.

In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4084-4089 ◽  
Author(s):  
Deniz Durali ◽  
Marie-Ghislaine de Goër de Herve ◽  
Julien Giron-Michel ◽  
Bruno Azzarone ◽  
Jean-François Delfraissy ◽  
...  
Keyword(s):  
B Cells ◽  
Nuclear Translocation ◽  
Interferon Γ ◽  
Interleukin 12 ◽  
Key Factors ◽  
Barr Virus ◽  
Human B Cells ◽  
Molecular Events ◽  
Ifn Γ ◽  
Epstein Barr

Abstract Two functionally distinct subsets of B cells that produce Th1- and Th2-like patterns of cytokines have recently been identified. Interleukin-12 (IL-12) is a critical immunoregulatory cytokine that promotes Th1 differentiation through activation of signal transducer and activator of transcription 4 (STAT4). IL-12 has been reported to induce interferon γ (IFN-γ) production in B cells, but the relevant signaling pathways are poorly documented. Here, in human primary B cells, we found a functional IL-12 receptor (IL-12R) that internalizes following IL-12 binding. IFN-γ and, to a lesser extent, IL-12 positively regulated the IL-12Rβ2 subunit but had no effect on IL-12Rβ1. On examining the effect of IL-12 on STAT4 and T-bet (2 key factors involved in IFN-γ promoter activation), we found that IL-12 induced the phosphorylation and nuclear translocation of STAT4. IL-12-dependent constitutive STAT4 activation was also observed in the Epstein-Barr virus (EBV)-transformed B-cell line RPMI 8866 that spontaneously produces IL-12. T-bet expression has been shown to be dependent on STAT1. IL-12 had no direct effect on STAT1 activation or T-bet expression in primary B cells. In contrast, IL-12-induced IFN-γ led to STAT1 activation, strong expression of T-bet, and IFN-γ expression. IL-12 therefore initiates a cascade of events in B cells, including STAT4 activation, IL-12Rβ2 up-regulation, IFN-γ production, and T-bet up-regulation, potentially leading to Th1-like differentiation. (Blood. 2003;102:4084-4089)

scholarly journals What Plasma Level of Interferon-γ Indicates in Systemic Chronic Active Epstein-Barr Virus Infection

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4529-4529
Author(s):  
Yu Uemura ◽  
Mayumi Yoshimori ◽  
Ayaka Ohashi ◽  
Tsuneaki Hirakawa ◽  
Naomi Wada ◽  
...  
Keyword(s):  
Nk Cells ◽  
Research Funding ◽  
Interferon Γ ◽  
Statistical Correlation ◽  
Epstein Barr Virus Infection ◽  
Mrna Levels ◽  
Barr Virus ◽  
Infected Cells ◽  
Ifn Γ ◽  
Epstein Barr

Abstract Background and Aim Systemic chronic active Epstein-Barr virus infection (sCAEBV) is an intractable and progressive disease of which the symptoms include persistent or recurrent inflammation and harboring EBV-infected clonally proliferating T- or NK-cells. 24% of sCAEBV patients progress to hemophagocytic lymphohistiocytosis (HLH), a life-threatening condition. (Blood Adv. 2020;4:p2918) The presence of HLH at hematopoietic stem cell transplantation is associated with poor survival in sCAEBV (BMT. 2016;15;p879). Interferon-γ (IFN-γ) plays pivotal roles in developing HLH, and antagonistic anti-IFN-γ antibody is effective against HLH (N Engl J Med 2020;382:p1811). In this study, we examined the plasma level of IFN-γ to investigate its impact on disease conditions of sCAEBV and its possibility as a therapeutic target. Methods sCAEBV was diagnosed based on following criteria which confirm with the definition of CAEBV in the WHO 2017 classification: (1) elevated EBV-DNA load in peripheral blood (PB) (>10 2.5 copies/μg DNA) (2) EBV infection of T- or NK-cells (see below) in the affected tissues or PB (3) systemic inflammatory symptoms persisting for more than three months (4) exclusion of other possible diagnoses: primary infection of EBV, autoimmune disease, congenital immunodeficiency, HIV, and other immunodeficiencies or underlying diseases with potential immunosuppression Patients who fulfilled all criteria (1) to (4) were diagnosed as sCAEBV. (Blood Adv. 2020;4(13):2918-2926.) We defined a patient's condition as active disease when presenting any of following persistent inflammation: fever, liver dysfunction, progressive skin lesions, vasculitis, or uveitis. The plasma concentration of IFN-γ was measured by high sensitivity cytokine beads assay. mRNA was measured by real-time RT-PCR using TaqMan ® system. Results We examined 18 sCAEBV patients (CD4 type n = 7, CD8 type n = 1, and CD56 type n = 10). Their IFN-γ plasma levels were significantly higher than those of healthy donors. The levels in sCAEBV patients with active disease were higher than those with inactive disease. The mRNA expression of IFN-γ was detected in EBV-infected cells of all patients. A patient whose plasma IFN-γ was extremely high harbored HLH with markedly high expression of the mRNA of IFN-γ in EBV-infected cells, but there was no statistical correlation between the plasma IFN-γ levels and the mRNA levels of EBV-infected cells. Discussion Our findings infer IFN-γ's role in the inflammation of sCAEBV. The mRNA expression of IFN-γ was detected in EBV-infected cells of all patients. We discovered earlier that STAT3, a responsible transcriptional factor for IFN-γ expression, is constitutively activated in EBV-infected T- or NK-cells of CAEBV (Oncotarget.2018; 9;31077). Thus, we suspected that IFN-γ is produced by EBV-infected cells. Meanwhile, there was no statistical correlation between the plasma IFN-γ levels and the mRNA levels of EBV-infected cells as a whole. The proliferation of non-infected immunocompetent cells, such as NK cells, CD8-positive T cells, macrophages, and histiocytes, are often detected in the lesions of CAEBV. These cells also possibly produce IFN-γ. sCAEBV patients accompanied by hemophagocytic lymphohistiocytosis (HLH) had significantly higher IFN-γ levels in the serum compared to those without HLH. There was a report on emapalumab's effect on primary HLH. We expect emapalumab, a human anti-IFN-γ, is effective to sCAEBV patients, particularly who is harboring HLH． Conclusion Plasma IFN-γ in sCAEBV indicates disease activity and potentially be a therapeutic target. Disclosures Arai: Abbvie GK: Honoraria; BMS: Honoraria; Chugai Pharmaceutical Co Ltd: Honoraria, Research Funding; Eisai Co Ltd: Research Funding; Abbott Japan LLC: Honoraria; Kyowa Kirin Co ltd: Honoraria, Research Funding; Ono Pharmaceutical Co ltd: Honoraria, Research Funding; Nippon Shinyaku Co Ltd: Honoraria, Research Funding; Otsuka Pharmaceutical Co ltd: Research Funding; Novartis Pharma KK: Honoraria; Takeda Pharmaceuticals Co Ltd: Honoraria, Research Funding; Shionogi & Co ltd: Research Funding; Asahi Kasei Pharma Corporation: Research Funding; Sanofi KK: Honoraria; Pfizer Japan Inc: Honoraria; Astellas Pharma Inc: Honoraria.

Quantitation, selection, and functional characterization of Epstein-Barr virus–specific and alloreactive T cells detected by intracellular interferon-γ production and growth of cytotoxic precursors

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1730-1740 ◽  
Author(s):  
Guenther Koehne ◽  
Katherine M. Smith ◽  
Teresa L. Ferguson ◽  
Roxanne Y. Williams ◽  
Glenn Heller ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Flow Cytometric Analysis ◽  
Interferon Γ ◽  
Cytotoxic T Cell ◽  
Barr Virus ◽  
Alloreactive T Cells ◽  
Ifn Γ ◽  
Epstein Barr

Techniques for the quantitation of virus-specific and alloantigen-reactive T cells vary in their measurement of clinically relevant T-cell effector populations, their sensitivity and quantitative accuracy, and the time required to obtain measurable results. We compared frequencies of Epstein-Barr virus (EBV)–specific and major alloantigen-reactive T cells as measured by flow cytometric analysis of responding T cells producing intracellular interferon-γ (IFN-γ) and by limiting-dilution analysis (LDA) of cytotoxic T-cell precursors (CTLp) at sequential time points during the generation of EBV-specific T-cell lines. The expansion of EBV-specific T lymphocytes and the depletion of alloreactive T cells in cultures of T cells sensitized with autologous EBV-transformed targets followed similar kinetics when measured by either method. Frequencies of EBV- specific T cells generating intracellular IFN-γ exceeded by 25- to 90-fold the frequencies of responding CTLp at each stage of expansion, whereas the frequencies of alloreactive T cells generating intracellular IFN-γ exceeded by 30- to 220-fold those detected by LDA. The assay that quantitated T cells producing IFN-γ yielded more reproducible and precise results than LDA. Furthermore, frequencies detected by the enumeration of T cells responding to immunodominant EBNA 3a and EBNA 3c peptides by IFN-γ production or their capacity to bind peptide-HLA tetramers were strikingly similar and represented significant fractions of T cells generating IFN-γ in response to autologous EBV B lymphoblastoid cell line. Functional analysis of responding viable T cells, fractionated on the basis of their secretion of IFN-γ, demonstrated that EBV-specific and alloantigen cytotoxic T cells were predominately or exclusively detected in the CD8+IFN-γ+ fraction of T cells. Strikingly, the CD4+IFN-γ+ cell fractions were not cytotoxic against EBV-transformed or allogeneic targets.

scholarly journals PIAS1 potentiates the anti-EBV activity of SAMHD1 through SUMOylation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Farjana Saiada ◽  
Kun Zhang ◽  
Renfeng Li
Keyword(s):  
Lytic Replication ◽  
Dependent Manner ◽  
Dna Viruses ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Barr Virus ◽  
Sumo Ligase ◽  
Lysine Residues ◽  
Epstein Barr ◽  
Rna And Dna

Abstract Background Sterile alpha motif and HD domain 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase (dNTPase) that restricts the infection of a variety of RNA and DNA viruses, including herpesviruses. The anti-viral function of SAMHD1 is associated with its dNTPase activity, which is regulated by several post-translational modifications, including phosphorylation, acetylation and ubiquitination. Our recent studies also demonstrated that the E3 SUMO ligase PIAS1 functions as an Epstein-Barr virus (EBV) restriction factor. However, whether SAMHD1 is regulated by PIAS1 to restrict EBV replication remains unknown. Results In this study, we showed that PIAS1 interacts with SAMHD1 and promotes its SUMOylation. We identified three lysine residues (K469, K595 and K622) located on the surface of SAMHD1 as the major SUMOylation sites. We demonstrated that phosphorylated SAMHD1 can be SUMOylated by PIAS1 and SUMOylated SAMHD1 can also be phosphorylated by viral protein kinases. We showed that SUMOylation-deficient SAMHD1 loses its anti-EBV activity. Furthermore, we demonstrated that SAMHD1 is associated with EBV genome in a PIAS1-dependent manner. Conclusion Our study reveals that PIAS1 synergizes with SAMHD1 to inhibit EBV lytic replication through protein–protein interaction and SUMOylation.

scholarly journals Effect ofTityus serrulatusvenom on cytokine production and the activity of murine macrophages

2002 ◽  
Vol 11 (1) ◽  
pp. 23-31 ◽  
Author(s):  
Vera L. Petricevich
Keyword(s):  
Cytokine Production ◽  
Peritoneal Macrophages ◽  
Interferon Γ ◽  
Enzyme Linked Immunosorbent Assay ◽  
No Production ◽  
Dependent Manner ◽  
Immune Functions ◽  
Macrophage Activity ◽  
Ifn Γ

The purpose of this study was to investigate the effects ofTityus serrulatusvenom (TSV) on murine peritoneal macrophages evaluated in terms of activation. The effects of crude TSV were analysed by detection of cytokines, oxygen intermediate metabolites (H2O2) and nitric oxide (NO) in supernatants of peritoneal macrophages. Several functional bioassays were employed including anin vitromodel for envenomating: cytotoxicity of TSV was assessed using the lyses percentage. Tumor necrosis factor (TNF) activity was assayed by measuring its cytotoxic activity on L-929 cells, and interleukin-6 (IL-6) and interferon-γ (IFN-γ) were assayed by enzyme-linked immunosorbent assay, whereas NO levels were detected by Griess colorimetric reactions in culture supernatant of macrophages incubated with TSV and subsequently exposed to either lipopolysaccharide or IFN-γ. Incubation of macrophages with TSV increased production of IL-6 and IFN-γ in a dose-dependent manner. TNF production was not detected in supernatants treated with TSV at any concentration. The increase in IL-6 secretion was not associated with concentration-dependent cytoxicity of TSV on these cells. These data suggest that the cytotoxicity does not appear to be the main cause of an increased cytokine production by these cells. Although NO is an important effector molecule in macrophage microbicidal activity, the inducing potential of the test compounds for its release was found to be very moderate, ranging from 125 to 800 mM. Interestingly, NO levels of peritoneal macrophages were increased after IFN-γ. Moreover, NO production had an apparent effect on macrophage activity. The results obtained here also shown that the TSV induces an important elevation in H2O2release. These results combined with NO production suggest that TSV possesses significant immunomodulatory activities capable of stimulating immune functionsin vitro.

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