Extracellular human T cell leukemia virus type I tax protein stimulates the proliferation of human synovial cells

Aono, Hiroyuki; Fujisawa, Kotaro; Hasunuma, Tomoko; Marriott, Susan J.; Nishioka, Kusuki

doi:10.1002/1529-0131(199811)41:11<1995::aid-art15>3.0.co;2-4

Cited by 21 publications

(4 citation statements)

References 59 publications

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“…Purified, recombinant Tax protein was shown to stimulate the proliferation of PBMC [18], activation of NF-B pathway, and expression of TNF-␤, Ig light chain, and IL-2 receptor ␣ expression on lymphoid cells [19 -21]. Extracellular Tax has also been shown to induce cytokine production from adult human microglial cells [22], TNF-␣ secretion from human neuronal cells [23], and proliferation of human synovial cells [24]. Serologic evidence also supports the presence of extracellular Tax; ϳ90% of HTLV-1-infected patients have antibodies to Tax [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Modulation of dendritic cell maturation and function by the Tax protein of human T cell leukemia virus type 1

Jain

Ahuja

Shimizu

et al. 2007

Journal of Leukocyte Biology

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Human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is characterized by the generation of an intense CTL cell response directed against the viral transactivator protein Tax. In addition, patients diagnosed with HAM/TSP exhibit rapid activation and maturation of dendritic cells (DC), likely contributing to the robust, Tax-specific CTL response. In this study, extracellular Tax has been shown to induce maturation and functional alterations in human monocyte-derived DC, critical observations being confirmed in freshly isolated myeloid DC. Tax was shown to promote the production of proinflammatory cytokines and chemokines involved in the DC activation process in a dose-and time-dependent manner. Furthermore, Tax induced the expression of DC activation (CD40, CD80, and CD86) and maturation (CD83) markers and enhanced the T cell proliferation capability of DC. Heat inactivation of Tax resulted in abrogation of these effects, indicating a requirement for the native structure of Tax, which was found to bind efficiently to the DC membrane and was internalized within a few hours, suggesting that extracellular Tax may possess an intracellular mechanism of action subsequent to entry. Finally, inhibitors of cellular signaling pathways, NF-κB, protein kinase, tyrosine kinase, and phospholipase C, were shown to inhibit Tax-mediated DC activation. This is the first study reporting the immunomodulatory effects of extracellular Tax in the DC compartment. These results suggest that DC, once exposed to Tax by uptake from the extracellular environment, can undergo activation, providing constant antigen presentation and costimulation to T cells, leading to the intense T cell proliferation and inflammatory responses underlying HAM/TSP.

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Section: Introductionmentioning

confidence: 99%

Modulation of dendritic cell maturation and function by the Tax protein of human T cell leukemia virus type 1

Jain

Ahuja

Shimizu

et al. 2007

Journal of Leukocyte Biology

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“…HTLV-I is known as an oncovirus which can induce ATL, and a recent report by Uchida et al including patients with ATL showed that mononuclear cells obtained from HTLV-I carriers exhibited upregulation of telomerase activity [14]. This evidence suggests that synoviocytes infected with HTLV-I have higher proliferation rates at least in part by the activation of the telomerase, since HTLV-I infection promotes the growth of synoviocytes [15,16,17]. Moreover, according to our recent data, telomerase activity is upregulated in cultured synoviocytes by adding bFGF [18].…”

Section: Discussionmentioning

confidence: 99%

Infection of synoviocytes with HTLV-I induces telomerase activity

Tsumuki

Nakazawa

Hasunuma

et al. 2001

Rheumatology International

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To investigate the mechanism of synovial hyperplasia by human T-lymphotropic virus type I (HTLV-I) infection, the enzymatic activity of telomerase and expression of telomerase-related factors in HTLV-I infected synoviocytes were examined. Cultured synoviocytes obtained from four patients with osteoarthritis (OA) and four with traumatic joint disease (TJD) were infected by HTLV-I. Telomerase activity was detected by telomeric repeat amplification protocol (TRAP) assay. Expression of telomerase-related mRNAs such as telomerase reverse transcriptase (hTERT), telomerase RNA component (hTERC), and telomeric repeat binding factor 2 (TRF2) were also examined. Telomerase activity was detected in all HTLV-I-infected synoviocytes but not in uninfected synoviocytes. A remarkable induction of hTERT mRNA was observed in four of eight HTLV-I-infected synoviocytes, whereas expressions of hTERC, TRF2, and TEP-1 mRNAs were not changed. Our results clearly demonstrate that HTLV-I upregulates telomerase activity in synoviocytes probably via upregulation of hTERT activity. These findings suggest that telomerase activation in synoviocytes has an important role in upregulated proliferative activity of HAAP synoviocytes.

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“…1997). In addition, Tax encoded by HTLV‐I pX gene upregulates the expression of IL‐6 (Aono et al . 1998).…”

Section: Discussionmentioning

confidence: 99%

Bone marrow cells carrying the env‐pX transgene play a role in the severity but not prolongation of arthritis in human T‐cell leukaemia virus type‐I transgenic rats: a possible role of articular tissues carrying the transgene in the prolongation of arthritis

Abe

Ishizu

Ikeda

et al. 2004

Int J Experimental Path

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Transgenic rats carrying the env-pX gene of human T-cell leukaemia virus type-I (env-pX rats) were immunized with type II collagen (CII), and chronological alterations of arthritis were compared with findings of collagen-induced arthritis (CIA) in wildtype Wistar-King-Aptekman-Hokudai (WKAH) rats. Arthritis induced by CII in env-pX rats was more severe and persisted longer than CIA in WKAH rats. To determine whether the phenomenon is caused mainly by the transgene-carrying lymphocytes or articular tissues, we immunized lethally irradiated env-pX and WKAH rats with reciprocal bone marrow cell (BMC) transplantation. A severe but transient arthritis was induced by CII in WKAH rats reconstituted by env-pX BMC (w/tB/CII rats). On the other hand, in env-pX rats reconstituted by WKAH BMC, arthritis persisted longer than in w/tB/CII rats, although the degree was less at an early phase after CII immunization. These findings suggest that articular tissues rather than the BMCs carrying the env-pX transgene play a role in the prolongation of arthritis in env-pX rats, although BMCs carrying the transgene are associated with the severity of arthritis. When inflammatory cytokines in synovial cells isolated from env-pX rats before they developed arthritis were examined, interleukin-6 (IL-6) was detected at a higher level than in synovial cells from WKAH rats, thus suggesting the critical role of IL-6 in env-pX arthritis.

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Extracellular human T cell leukemia virus type I tax protein stimulates the proliferation of human synovial cells

Abstract: Our results suggest that extracellular Tax can regulate the expression of endogenous cellular genes in synovial cells and may contribute to the NF-kappaB-mediated synovial hyperplasia.

Cited by 21 publications

References 59 publications

Modulation of dendritic cell maturation and function by the Tax protein of human T cell leukemia virus type 1

Modulation of dendritic cell maturation and function by the Tax protein of human T cell leukemia virus type 1

Infection of synoviocytes with HTLV-I induces telomerase activity

Bone marrow cells carrying the env‐pX transgene play a role in the severity but not prolongation of arthritis in human T‐cell leukaemia virus type‐I transgenic rats: a possible role of articular tissues carrying the transgene in the prolongation of arthritis

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