Interleukin-12 Expression in B Cells by Transformation with Epstein–Barr Virus

Yoshimoto, Takayuki; Nagase, Hisashi; Yoneto, Toshihiko; Inoue, Jun‐ichiro; Nariuchi, Hideo

doi:10.1006/bbrc.1998.9693

Cited by 11 publications

(8 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ability to produce IL-12 is a fundamental property of monocytes and dendritic cells in various infectious and autoimmune diseases (2,(35)(36)(37)(38). In the present study, we provide evidence that the IL-12 p40 promoter in primary CD14 ϩ blood monocytes is tightly regulated in vivo by the coordinated binding of various trans-acting proteins such as C/EBP␤, NF-B p50/p65, and PU.1.…”

Section: Discussionsupporting

confidence: 53%

Regulation of IL-12 p40 Promoter Activity in Primary Human Monocytes: Roles of NF-κB, CCAAT/Enhancer-Binding Protein β, and PU.1 and Identification of a Novel Repressor Element (GA-12) That Responds to IL-4 and Prostaglandin E2

Becker

Wirtz

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

Appropriate regulation of IL-12 expression is critical for cell-mediated immune responses. In the present study, we have analyzed the regulation of IL-12 p40 promoter activity in primary human monocytes in vivo. Accordingly, we analyzed the p40 promoter by in vivo footprinting in resting and activated primary human blood CD14+ monocytes. Interestingly, footprints at binding sites for trans-activating proteins such as C/EBP, NF-κB, and ETS were only found upon stimulation with LPS and IFN-γ. In contrast, a footprint over a purine-rich sequence at −155, termed GA-12 (GATA sequence in the IL-12 promoter), was observed in resting, but not activated, cells. Further characterization of this site revealed specific complex formation at a protected GATA core motif in unstimulated primary monocytes and RAW264.7 macrophages. Mutagenesis within the GA-12 sequence caused a significant up-regulation of inducible IL-12 p40 promoter activity in both transient and stable transfection systems, suggesting a repressor function of this site. Furthermore, binding activity of the GA-12 binding protein GAP-12 was increased by treatment with two potent inhibitors of IL-12 expression, IL-4 and PGE2. Finally, we observed that IL-4-mediated repression of IL-12 p40 promoter activity is critically dependent on an intact GA-12 sequence. In summary, our data underline the complex regulation of the human IL-12 p40 promoter and identify GA-12 as a potent, novel repressor element that mediates IL-4-dependent suppression of inducible promoter activity in monocytes. Regulation of GAP-12 binding may thus modulate IL-12 p40 gene expression.

show abstract

Section: Discussionsupporting

confidence: 53%

Regulation of IL-12 p40 Promoter Activity in Primary Human Monocytes: Roles of NF-κB, CCAAT/Enhancer-Binding Protein β, and PU.1 and Identification of a Novel Repressor Element (GA-12) That Responds to IL-4 and Prostaglandin E2

Becker

Wirtz

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Additionally IFNγ, found induced in NPC tissues, was detected at approximately 2 to 3 fold higher levels in the St2 and St5 tissues, with reduced levels in serum compared to controls, a pattern also observed with IL-10 and the murine IL-8 analogues. The cytokines IL-12 (proposed to be induced by LMP1 in B-cells [30]), IL-2, IL-3 (and receptor IL-3Rβ) and the pro-inflammatory IL-1β were detected at higher levels in St2 and St5 tissues than controls. The angiogenic factor vascular endothelial growth factor (VEGF) was also detected at higher levels in the tissue samples (2x) and was previously observed to be induced in the transgenic samples by western blotting [20].…”

Section: Resultsmentioning

confidence: 99%

Lymphocyte deficiency limits Epstein-Barr virus latent membrane protein 1 induced chronic inflammation and carcinogenic pathology in vivo

et al. 2011

View full text Add to dashboard Cite

BackgroundThe importance of the malignant cell environment to its growth and survival is becoming increasingly apparent, with dynamic cross talk between the neoplastic cell, the leukocyte infiltrate and the stroma. Most cancers are accompanied by leukocyte infiltration which, contrary to an anticipated immuno-protective role, could be contributing to tumour development and cancer progression. Epstein-Barr virus (EBV) associated cancers, including nasopharyngeal carcinoma and Hodgkin's Disease, show a considerable leukocyte infiltration which surrounds the neoplastic cells, raising the questions as to what role these cells play in either restricting or supporting the tumour and what draws the cells into the tumour. In order to begin to address this we have studied a transgenic model of multistage carcinogenesis with epithelial expression of the EBV primary oncoprotein, latent membrane protein 1 (LMP1). LMP1 is expressed particularly in the skin, which develops a hyperplastic pathology soon after birth.ResultsThe pathology advances with time leading to erosive dermatitis which is inflamed with a mixed infiltrate involving activated CD8+ T-cells, CD4+ T-cells including CD4+/CD25+/FoxP3+ Treg cells, mast cells and neutrophils. Also significant dermal deposition of immunoglobulin-G (IgG) is observed as the pathology advances. Along with NF-kappaB activation, STAT3, a central factor in inflammation regulation, is activated in the transgenic tissue. Several inflammatory factors are subsequently upregulated, notably CD30 and its ligand CD153, also leukocyte trafficking factors including CXCL10, CXCL13, L-selectin and TGFβ1, and inflammatory cytokines including IL-1β, IL-3 and the murine IL-8 analogues CXCL1, CXCL2 and CXCL5-6, amongst others. The crucial role of mature T- and/or B-lymphocytes in the advancing pathology is demonstrated by their elimination, which precludes mast cell infiltration and limits the pathology to an early, benign stage.ConclusionsLMP1 can lead to the activation of several key factors mediating proliferation, angiogenesis and inflammation in vivo. With the initiation of an inflammatory programme, leukocyte recruitment follows which then itself contributes to the progressing pathology in these transgenic mice, with a pivotal role for B-and/or T-cells in the process. The model suggests a basis for the leukocyte infiltrate observed in EBV-associated cancer and its supporting role, as well as potential points for therapeutic intervention.

show abstract

“…thase (iNOS) in vitro. [19][20][21][22][23] Interestingly, the levels of IL-8, IL-12, RANTES and MCP-1 are increased in the BAL of LTR with BOS 24,25 and the expression of iNOS is elevated. 26 Possibly, EBV contributes to the development of BOS by inducing the production of these cytokines.…”

Section: Discussionmentioning

confidence: 98%

Detection of Epstein–Barr virus DNA in peripheral blood is associated with the development of bronchiolitis obliterans syndrome after lung transplantation

Welte

Fühner

Simon

et al. 2009

Journal of Clinical Virology

View full text Add to dashboard Cite

Interleukin-12 Expression in B Cells by Transformation with Epstein–Barr Virus

Cited by 11 publications

References 39 publications

Regulation of IL-12 p40 Promoter Activity in Primary Human Monocytes: Roles of NF-κB, CCAAT/Enhancer-Binding Protein β, and PU.1 and Identification of a Novel Repressor Element (GA-12) That Responds to IL-4 and Prostaglandin E2

Regulation of IL-12 p40 Promoter Activity in Primary Human Monocytes: Roles of NF-κB, CCAAT/Enhancer-Binding Protein β, and PU.1 and Identification of a Novel Repressor Element (GA-12) That Responds to IL-4 and Prostaglandin E2

Lymphocyte deficiency limits Epstein-Barr virus latent membrane protein 1 induced chronic inflammation and carcinogenic pathology in vivo

Detection of Epstein–Barr virus DNA in peripheral blood is associated with the development of bronchiolitis obliterans syndrome after lung transplantation

Contact Info

Product

Resources

About