Transcriptional activation of the interleukin-6 gene by HTLV-1 p40tax through an NF-κB-like binding site

doi:10.1016/0165-2478(93)90026-X

Immunology Letters

Volume 37, Issues 2–3, August 1993, Pages 159-165

https://doi.org/10.1016/0165-2478(93)90026-X Get rights and content

Abstract

The interleukin-6 (IL-6) gene is expressed by various stimuli including cytokines or viral infections, such as human T-cell leukemia virus type I (HTLV-1). However, it has not been well established how HTLV-1 induces the expression of the IL-6 gene. In the present study, we demonstrated that HTLV-1-derived transactivator protein, p40tax, could stimulate endogenous IL-6 gene expression. Furthermore, we showed that the NF-κB binding site (IL-6κB site) located between −74 and −62 upstream of the cap site of the IL-6 gene was an essential cis-acting element for p40tax-mediated transaction of the IL-6 gene expression by utilizing a series of 5′ deletion mutants of the IL-6 5′ flanking region as well as a construct with a mutated IL-6κB site. We identified the presence of two nuclear factor complexes that bound to the IL-6κB site. One was constitutively expressed, and the other was inducible by p40tax. Taken together, HTLV-1 p40tax directly induces IL-6 gene expression through the IL-6κB site, indicating the close association between IL-6 overproduction and HTLV-1 infection.

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The HTLV-I protein Tax is capable of activating both the canonical and the noncanonical NF-κB pathways by interacting with the IκB kinase subunits, leading to the release of NF-κB from cytoplasmic sequestration.10,11 The NF-κB–dependent induction of pro-inflammatory cytokines such as IL-6,12 IL-9,13 and IL-15,14 and the induction of IL-2 receptorα (IL-2Rα)15 in HTLV-I–infected cells suggests that NF-κB activation may play a critical role in the development of diseases associated with HTLV-I infection. To further define the contribution of NF-κB activation to the pathogenesis of HAM/TSP, we compared NF-κB activation in peripheral blood mononuclear cells (PBMCs) from subjects with HAM/TSP against that of healthy donors, and examined the relationship of HTLV-I viral protein expression and NF-κB activation.
The human T-lymphotropic virus type I (HTLV-I) causes a chronic inflammatory disorder of the central nervous system termed HTLV-I–associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-I encodes a protein known to activate several host-signaling pathways involved in inflammation, such as the nuclear factor-κB (NF-κB). The contribution of the NF-κB pathway to the pathogenesis of HAM/TSP, however, has not been fully defined. We show evidence of canonical NF-κB activation in short-term cultures of peripheral blood mononuclear cells (PBMCs) from subjects with HAM/TSP. NF-κB activation was closely linked to HTLV-I viral protein expression. The NF-κB activation in HAM/TSP PBMCs was reversed by a novel small-molecule inhibitor that demonstrates potent and selective NF-κB antagonist activity. Inhibition of NF-κB activation led to a reduction in the expression of lymphocyte activation markers and resulted in reduced cytokine signaling in HAM/TSP PBMCs. Furthermore, NF-κB inhibition led to a reduction in spontaneous lymphoproliferation, a key ex vivo correlate of the immune activation associated with HAM/TSP. These results indicate that NF-κB activation plays a critical upstream role in the immune activation of HAM/TSP, and identify the NF-κB pathway as a potential target for immunomodulation in HAM/TSP.
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pGL3-GPVI (-208/+29M1), pGL3-GPVI (-208/+29M2), and pGL3-GPVI (-79/+29M3) were generated by introducing mutations of GATA (AGATAA to CGCTTA), the first YY1 (GATGAG to GCTTAG), and third YY1 (CTCATC to CTAAGC) binding sites, respectively. Reporter plasmids, pGL3-c-fos (-700/+53), pGL3-FcϵRIα (-605/+29), and mPGV-B-il-6 (-181/+14) were described previously (9, 20, 21). Luciferase assays using HEK293 and HEK293T cells were performed as previously described (22).
OTT/RBM15-BSAC/MAL/MKL1/MRTF-A was identified as a fusion transcript generated by t(1;22)(p13;q13) in acute megakaryoblastic leukemia. Previous studies have shown that BSAC (basic, SAP, and coiled-coil domain) activates the promoters containing CArG boxes via interaction with serum response factor, and OTT (one twenty-two) negatively regulates the development of megakaryocytes and myeloid cells. However, the mechanism by which OTT-BSAC promotes leukemia is largely unknown. Here we show that OTT-BSAC, but not BSAC or OTT strongly activates several promoters containing a transcription factor Yin Yang 1-binding sequence. In addition, although BSAC predominantly localizes in the cytoplasm and its nuclear translocation is considered to be regulated by the Rho-actin signaling pathway, OTT-BSAC exclusively localizes in the nucleus. Moreover, OTT interacts with histone deacetylase 3, but this interaction is abolished in OTT-BSAC. Collectively, these functional and spatial changes of OTT and BSAC caused by the fusion might perturb their functions, culminating in the development of acute megakaryoblastic leukemia.
Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-eell leukemia cells by a paracrine mechanism
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In addition, Tax activates other cellular transcription factors, such as NF-κB. Tax is associated with the expression of cellular genes,5 including the cytokine6-10 and cytokine receptor genes.7,11-13 It has been suggested that the dysregulation of cytokines and their receptors in HTLV-I–infected persons may play an important role in the early course of disease via autocrine stimulation.9,11
The etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type I (HTLV-I). The HTLV-I protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-κB motif in its proximal promoter, whereas IL-9 receptor-α (IL-9Rα) expression is not induced by Tax. However, supporting a role for IL-9/IL-9Rα in ATL, a neutralizing monoclonal antibody directed toward IL-9Rα inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Rα on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9Rα/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism.
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Human T cell leukemia virus 1 (HTLV-1) gene expression is regulated by both the viral Tax protein and by cellular transcriptional factors. We have previously shown that immune activation stimuli such as phorbol esters (PMA) and phytohemagglutinin (PHA) cooperate with HTLV-1 Tax expression to enhance HTLV-1 gene expression in infected T cells through increased activity of the HTLV-1 LTR. We now extend these studies to demonstrate roles for the T cell receptor complex, Lck, and Ras molecules in the coactivation of the HTLV-1 LTR by Tax and T cell activation stimuli. We also observe coactivation of Tax-responsive cellular promoter elements containing NF-κB and serum response factor (SRF) binding sites by Tax and T cell activation stimuli. These results suggest a model whereby T cell receptor stimulation and Tax expression coactivate HTLV-1 gene expression and cellular gene expression, enhancing activation of latent HTLV-1 and expression of cellular genes involved in disease pathogenesis.
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Transcriptional activation of the interleukin-6 gene by HTLV-1 p40tax through an NF-κB-like binding site

Abstract

Res. Immunol.

Lancet

Annu. Rev. Immunol.

Chem. Immunol.

Arthr. Rheum.

Eur. J. Immunol.

Arthr. Rheum.

J. Immunol.

Eur. J. Immunol.

Arthr. Rheum.

J. Immunol.

J. Exp. Med.

J. Immunol.

J. Exp. Med.

EMBO J.

Mol. Cell. Biol.

Eur. J. Immunol.

J. Exp. Med.

J. Exp. Med.