scholarly journals Regulation of Bovine Leukemia Virus taxand pol mRNA Levels by Interleukin-2 and -10

1999 ◽  
Vol 73 (10) ◽  
pp. 8427-8434 ◽  
Author(s):  
Dohun Pyeon ◽  
Gary A. Splitter
Keyword(s):  
Bovine Leukemia Virus ◽  
Mononuclear Cells ◽  
Leukemia Virus ◽  
Interleukin 2 ◽  
Disease Stage ◽  
Mrna Levels ◽  
Soluble Factor ◽  
Early Disease ◽  
P24 Protein ◽  
Disease Stages

ABSTRACT Recently, particular cytokines have been identified to affect progression of a variety of diseases and retrovirus infections. Previously, we demonstrated that interleukin-2 (IL-2), IL-12, and gamma interferon increased in peripheral blood mononuclear cells (PBMCs) from animals with early disease and decreased in PBMCs from animals with late disease stages of bovine leukemia virus (BLV) infection. In contrast, IL-10 increased with disease progression. To examine the effects of these cytokines on BLV expression, BLV tax andpol mRNA and p24 protein were quantified by competitive PCR and immunoblotting, respectively. IL-10 inhibited BLV taxand pol mRNA levels in BLV-infected PBMCs; however, the inhibitory effect of IL-10 was prevented in PBMCs depleted of monocytes and/or macrophages (monocyte/macrophages). To determine whether these factors were secreted or monocyte/macrophage associated, monocyte/macrophage-depleted PBMCs were cultured with isolated monocyte/macrophages in transwells where contact between monocyte/macrophages and nonadherent PBMCs was blocked. BLVtax and pol mRNA levels increased in transwell cultures similar to cultures containing nonseparated cells, and IL-10 addition inhibited the increase of BLV tax andpol mRNA. These results suggest that monocyte/macrophages secrete soluble factor(s) that increases BLV mRNA levels and that secretion of these soluble factor(s) could be inhibited by IL-10. In contrast, IL-2 increased BLV tax and pol mRNA and p24 protein production. Thus, IL-10 production by BLV-infected animals with late stage disease may serve to control BLV mRNA levels, while IL-2 may increase BLV mRNA in the early disease stage. To determine a correlation between cell proliferation and BLV expression, the effect of IL-2 and IL-10 on PBMC proliferation was tested. As anticipated, IL-2 stimulated while IL-10 suppressed antigen-specific PBMC proliferation. The present study, combined with our previous findings, suggests that increased IL-10 production in late disease stages suppresses BLV mRNA levels, while IL-2-activated immune responses stimulate BLV expression by BLV-infected B cells.

scholarly journals Prostaglandin E2 Increases Bovine Leukemia Virustax and pol mRNA Levels via Cyclooxygenase 2: Regulation by Interleukin-2, Interleukin-10, and Bovine Leukemia Virus

2000 ◽  
Vol 74 (12) ◽  
pp. 5740-5745 ◽  
Author(s):  
Dohun Pyeon ◽  
Francisco J. Diaz ◽  
Gary A. Splitter
Keyword(s):  
Immune Response ◽  
Bovine Leukemia Virus ◽  
Leukemia Virus ◽  
Interleukin 2 ◽  
Cyclooxygenase 2 ◽  
Disease Stage ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Cox 2

ABSTRACT Prostaglandin E2 (PGE2), produced by macrophages, has important immune regulatory functions, suppressing a type 1 immune response and stimulating a type 2 immune response. Type 1 cytokines (interleukin-2 [IL-2], IL-12, and gamma interferon) increase in freshly isolated peripheral blood mononuclear cells (PBMCs) of animals with an early disease stage of bovine leukemia virus (BLV) infection, while IL-10 increases in animals with a late disease stage. Although IL-10 has an immunosuppressive role in the host immune system, IL-10 also inhibits BLV tax and polmRNA levels in vitro. In contrast, IL-2 stimulates BLVtax and pol mRNA and p24 protein expression in cultured PBMCs. The inhibitory effect of IL-10 on BLV expression depends on soluble factors secreted by macrophages. Thus, we hypothesized that PGE2, a cyclooxygenase 2 (COX-2) product of macrophages, may regulate BLV expression. Here, we show that the level of COX-2 mRNA was decreased in PBMCs treated with IL-10, while IL-2 enhanced the level of COX-2 mRNA. Addition of PGE2 stimulated BLV tax and polmRNA levels and reversed the IL-10 inhibition of BLV mRNA. In addition, the specific COX-2 inhibitor, NS-398, inhibited the amount of BLV mRNA detected. Addition of PGE2 increased BLV tax mRNA regardless of NS-398 addition. PGE2 inhibited antigen-specific PBMC stimulation, suggesting that stimulation of BLVtax and pol mRNA levels by PGE2 is independent of cell proliferation. These findings suggest that macrophage-derived COX-2 products, such as PGE2, regulate virus expression and disease progression in BLV infection.

scholarly journals Antiviral Activity of Shiga Toxin 1: Suppression of Bovine Leukemia Virus-Related Spontaneous Lymphocyte Proliferation

2000 ◽  
Vol 68 (8) ◽  
pp. 4462-4469 ◽  
Author(s):  
Witold A. Ferens ◽  
Carolyn J. Hovde
Keyword(s):  
Antiviral Activity ◽  
Shiga Toxin ◽  
Bovine Leukemia Virus ◽  
Lymphocyte Proliferation ◽  
Mononuclear Cells ◽  
Leukemia Virus ◽  
Interleukin 2 ◽  
Pokeweed Mitogen ◽  
Potent Antiviral Activity ◽  
The Impact

ABSTRACT Human infections with Shiga toxin (Stx)-producing Escherichia coli (STEC) cause hemorrhagic colitis. The Stxs belong to a large family of ribosome-inactivating proteins (RIPs) that are found in a variety of higher plants and some bacteria. Many RIPs have potent antiviral activity for the plants that synthesize them. STEC strains, both virulent and nonvirulent to humans, are frequently isolated from healthy cattle. Interestingly, despite intensive investigations, it is not known why cattle carry STEC. We tested the hypothesis that Stx has antiviral properties for bovine viruses by assessing the impact of Stx type 1 (Stx1) on bovine peripheral blood mononuclear cells (PBMC) from cows infected with bovine leukemia virus (BLV). PBMC from BLV-positive animals invariably displayed spontaneous lymphocyte proliferation (SLP) in vitro. Stx1 or the toxin A subunit (Stx1A) strongly inhibited SLP. Toxin only weakly reduced the pokeweed mitogen- or interleukin-2-induced proliferation of PBMC from normal (BLV-negative) cows and had no effect on concanavalin A-induced proliferation. The toxin activity in PBMC from BLV-positive cattle was selective for viral SLP and did not abrogate cell response to pokeweed mitogen- or interleukin-2-induced proliferation. Antibody to virus or Stx1A was most effective at inhibiting SLP if administered at the start of cell culture, indicating that both reagents likely interfere with BLV-dependent initiation of SLP. Stx1A inhibited expression of BLV p24 protein by PBMC. A well-defined mutant Stx1A (E167D) that has decreased catalytic activity was not effective at inhibiting SLP, suggesting the inhibition of protein synthesis is likely the mechanism of toxin antiviral activity. Our data suggest that Stx has potent antiviral activity and may serve an important role in BLV-infected cattle by inhibiting BLV replication and thus slowing the progression of infection to its malignant end stage.

scholarly journals Cellular Immune Response to Interferon-Τ in Peripheral Blood Mononuclear Cells of Japanese Black Cattle with Bovine Leukemia Virus Infection / Imunski Odgovor Mononuklearnih Ćelija Periferne Krvi Na Interferon-Τ Kod Infekcije Virusom Leukemije Japanskog Crnog Govečeta

2015 ◽  
Vol 65 (2) ◽  
pp. 287-296
Author(s):  
Kakinuma Sei-Ichi ◽  
Izawa Tomohiro ◽  
Matsuda Kei-Ichi ◽  
Konnai Satoru ◽  
Maeda Yosuke ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Bovine Leukemia Virus ◽  
Mononuclear Cells ◽  
Leukemia Virus ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Healthy Cattle ◽  
Blood Mononuclear Cells ◽  
Cellular Immune

γ IFN-τ is a type I interferon, and it is known to be non-virus inducible in ruminants. IFN-τ reduced syncytium formation by PBMC obtained from BLV infected cattle in vitro. In order to clarify the effects of IFN-τ on cellular immune function in Japanese Black (JB) cattle with bovine leukemia virus (BLV) infection, immune related factors of peripheral blood mononuclear cells (PBMC) were analyzed using IFN-τ as a stimulator. Thirty-two JB cattle were used in this investigation, and these cattle were divided into three groups: cattle with enzootic bovine leucosis (EBL) (EBL Group, N=7), clinically healthy cattle with BLV infection (Carrier Group, N=13), and clinically healthy cattle without BLV infection (non-Carrier Group, N=12). A number of mRNA expressions of interleukin-12 and interferon (IFN)-as immune cell activating cytokines, perforin and granulysin as cytotoxic factors, and myxovirus resistance protein (MX)-1 and MX-2 as anti-virus factors of PBMC were analyzed after culturing cells with phytohemagglutinin (PHA) or IFN-τ. The basal mRNA levels of perforin and granulysin in the Carrier Group were significantly higher than those in the non-Carrier Group. Also, significantly higher basal mRNA levels of MX-1 and MX-2 in the EBL Group were detected compared with the non-Carrier Group. The mRNA expressions of perforin and granulysin in PBMC stimulated with PHA were higher in the Carrier Group than those in the non-Carrier Group. There were significantly higher mRNA levels of MX-1 and MX-2 in PBMC stimulated with IFN-τ in the EBL Group compared with those in the non-Carrier Group. These results suggest an enhanced sensitivity of anti-virus reaction in PBMC by IFN-τ treatment in JB cattle with EBL.

scholarly journals Involvement of Glutathione as a Mechanism of Indirect Protection against Spontaneous Ex Vivo Apoptosis Associated with Bovine Leukemia Virus

2004 ◽  
Vol 78 (12) ◽  
pp. 6180-6189 ◽  
Author(s):  
Teresa Sanchez Alcaraz ◽  
Pierre Kerkhofs ◽  
Michal Reichert ◽  
Richard Kettmann ◽  
Luc Willems
Keyword(s):  
Cell Death ◽  
B Lymphocytes ◽  
Bovine Leukemia Virus ◽  
Mononuclear Cells ◽  
Phorbol Esters ◽  
Ex Vivo ◽  
Leukemia Virus ◽  
Infected Sheep ◽  
Host Cells ◽  
Spontaneous Apoptosis

ABSTRACT Viruses have developed strategies to counteract the apoptotic response of the infected host cells. Modulation of apoptosis is also thought to be a major component of viral persistence and progression to leukemia induced by retroviruses like human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV). Here, we analyzed the mechanism of ex vivo apoptosis occurring after isolation of peripheral blood mononuclear cells from BLV-infected sheep. We show that spontaneous apoptosis of ovine B lymphocytes requires at least in part a caspase 8-dependent pathway regardless of viral infection. Cell death is independent of cytotoxic response and does not involve the tumor necrosis factor alpha/NF-κB/nitric oxide synthase/cyclooxygenase pathway. In contrast, pharmaceutical depletion of reduced glutathione (namely, γ-glutamyl-l-cysteinyl-glycine [GSH]) by using ethacrynic acid or 1-pyrrolidinecarbodithioic acid specifically reverts inhibition of spontaneous apoptosis conferred indirectly by protective BLV-conditioned media; inversely, exogenously provided membrane-permeable GSH-monoethyl ester restores cell viability in B lymphocytes of BLV-infected sheep. Most importantly, intracellular GSH levels correlate with virus-associated protection against apoptosis but not with general inhibition of cell death induced by polyclonal activators, such as phorbol esters and ionomycin. Finally, inhibition of apoptosis does not correlate with the activities of GSH peroxidase and GSH reductase. In summary, our data fit into a model in which modulation of the glutathione system is a key event involved in indirect inhibition of apoptosis associated with BLV. These observations could have decisive effects during therapeutic treatment of δ-retroviral pathogenesis.

scholarly journals Involvement of lncRNA IL21-AS1 in interleukin-2 and T follicular regulatory cell activation in systemic lupus erythematosus

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
He Hao ◽  
Shingo Nakayamada ◽  
Naoaki Ohkubo ◽  
Kaoru Yamagata ◽  
Mingzeng Zhang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
T Cell Subsets ◽  
Mrna Levels ◽  
Systemic Lupus ◽  
Allelic Discrimination

Abstract Background The single nucleotide polymorphism (SNP) rs62324212, located in IL21 antisense RNA 1 (IL21-AS1), has been identified as a genetic risk variant associated with systemic lupus erythematosus (SLE). We aimed to probe the characteristics of IL21-AS1 and explore its clinical relevance focusing on T helper subsets and disease activity in patients with SLE. Methods rs62324212 genotyping was determined using allelic discrimination by quantitative PCR. Gene expression in peripheral blood mononuclear cells and cell surface markers in CD4+ T cells were analyzed using PCR and flow cytometry. The association among IL21-AS1, CD4+ T cell subsets, and SLE disease activity was accessed. Results Ensembl Genome Browser analysis revealed that rs62324212 (C>A) was located in the predicting enhancer region of IL21-AS1. IL21-AS1 was expressed in the nucleus of CD4+ T and B cells, but its expression was decreased in patients with SLE. IL21-AS1 expression was positively correlated with mRNA levels of IL-2 but not IL-21, and it was associated with the proportion of activated T follicular regulatory (Tfr) cells. Furthermore, we observed a significant negative correlation between IL21-AS1 expression and disease activity in patients with SLE (n = 53, p < 0.05). Conclusion IL21-AS1 has an effect on disease activity through an involvement of IL-2-mediated activation of Tfr cells in SLE. Thus, targeting the IL21-AS1 may provide therapeutic approaches for SLE.

Involvement of lncRNA IL21-AS1 in Interleukin-2 and T Follicular Regulatory Cell Activation in Systemic Lupus Erythematosus

2021 ◽  
Author(s):  
He Hao ◽  
Shingo Nakayamada ◽  
Naoaki Ohkubo ◽  
Kaoru Yamagata ◽  
Mingzeng Zhang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
T Cell Subsets ◽  
Mrna Levels ◽  
Systemic Lupus ◽  
Allelic Discrimination

Abstract Background The single nucleotide polymorphism (SNP) rs62324212, located in IL21 antisense RNA 1 (IL21-AS1), has been identified as a genetic risk variant associated with systemic lupus erythematosus (SLE). We aimed to probe the characteristics of IL21-AS1 and explore its clinical relevance focusing T helper subsets and disease activity in patients with SLE. Methods rs62324212 genotyping was determined using allelic discrimination by quantitative PCR. Gene expression in peripheral blood mononuclear cells and cell surface markers in CD4+ T cells were analyzed using PCR and flow cytometry. The association among IL21-AS1, CD4+ T cell subsets and SLE disease activity were accessed. Results Ensembl Genome Browser analysis revealed that rs62324212 (C > A) was located in the predicting enhancer region of IL21-AS1. IL21-AS1 was expressed in the nucleus of CD4+ T and B cells, but its expression was decreased in patients with SLE. IL21-AS1 expression was positively correlated with mRNA levels of IL-2 but not IL-21, and it was associated with the proportion of activated T follicular regulatory (Tfr) cells. Furthermore, we observed a significant negative correlation between IL21-AS1 expression and disease activity in patients with SLE (n = 53, p < 0.05). Conclusion IL21-AS1 has an effect on disease activity through an impairment of IL-2-mediated activation of Tfr cell in SLE. Thus, targeting the IL21-AS1 may provide therapeutic approaches for SLE.

scholarly journals Lymphocyte Response to Genetically Engineered Bovine Leukemia Virus Proteins in Persistently Lymphocytic Cattle from Israel and the U.S.

1995 ◽  
Author(s):  
Gary Splitter ◽  
Zeev Trainin ◽  
Yacov Brenner
Keyword(s):  
T Cell ◽  
Mrna Expression ◽  
Protein Production ◽  
Leukemia Virus ◽  
Lymphocyte Subpopulations ◽  
Competitive Pcr ◽  
P24 Protein ◽  
Cox 2 ◽  
Disease Stages

The goal of this proposal was to identify proteins of BLV recognized by lymphocyte subpopulations and determine the contribution of these proteins to viral pathogenesis. Our hypothesis was that BLV pathogenesis is governed by the T-cell response and that the immune system likely plays an important role in controlling the utcome of infection. Our studies presented in ths final report demonstrate that T cell competency declines with advancing stages of infection. Dramatic differences were observed in lymphocyte proliferation to recombinant proteins encoded by BLV gag (p12, p15, and p24) and env (gp30 and gp15) genes in different disease stages. Because retroviruses are known to mutate frequently, examinatin of infected cattle from both Israel and the United States will likely detect variability in the immune response. This combined research approach provides the first opportunity to selectively address the importance of T-cell proliferation to BLV proteins and cytokines produced during different stages of BLV infection. Lack of this information regarding BLV infection has hindered understanding lympocyte regulation of BLV pathogenesis. We have developed the essential reagents necessary to determine the prominence of different lymphocyte subpopulations and cytokines produced during the different disease stages within the natural host. We found that type 1 cytokines (IL-2 and IFN-g) increased in PBMCs from animals in early disease, and decreasd in PBMCs from animals in late disease stages of BLV infection, while IL-10, increased with disease progression. Recently, a dichotomy between IL-12 and IL-10 has emerged in regards to progression of a variety of diseases. IL-12 activates type 1 cytokine production and has an antagonistic effect on type 2 cytokines. Here, using quantitative competitive PCR, we show that peripheral blood mononuclear cells from bovine leukemia virus infected animals in the alymphocytotic disease stage express increased amount of IL-12 p40 mRNA. In contrast, IL-12 p40 mRNA expression by PL animals was significantly decreased compared to normal and alymphocytotic animals. To examine the functions of these cytokines on BLV expression, BLV tax and pol mRNA expression and p24 protein production were quantified by competitive PCR, and by immunoblotting, respectively. IL-10 inhibited BLV tax and pol mRNA expression by BLV-infected PBMCs. In addition, we determined that macrophages secret soluble factor(s) that activate BLV expression, and that secretion of the soluble factor(s) could be inhibited by IL-10. In contrast, IL-2 increased BLV tax and pol mRNA, and p24 protein production. These findings suggest that macrophages have a key role in regulating BLV expression, and IL-10 produced by BLV-infected animals in late disease stages may serve to control BLV expression, while IL-2 in the early stage of disease may activate BLV expression. PGE2 is an important immune regulator produced only by macrophages, and is known to facilitate HIV replication. We hypothesized that PGE2 may regulate BLV expression. Here, we show that cyclooxygenase-2 (COX-2) mRNA expression was decreased in PBMCs treated with IL-10, while IL-2 enhanced COX-2 mRNA expression. In contrast, addition of PGE2 stimulated BLV tax and pol mRNA expression. In addition, the specific COX-2 inhibitor, NS-398, inhibited BLV expression, while addition of PGE2 increased BLV tax expression regardless of NS-398. These findings suggest that macrophage derived cyclooxygenase -2 products, such as PGE2, may regulate virus expression and disease rogression in BLV infection, and that cytokines (IL-2 and IL-10) may regulate BLV expression through PGE2 production.

Sign in / Sign up

Export Citation Format

Share Document