IL-2- and STAT5-regulated cytokine gene expression in cells expressing the Tax protein of HTLV-1

Fung, Michelle M; Chu, Yen-Lin; Fink, J. Lynn; Wallace, Anne; McGuire, Kathleen L.

doi:10.1038/sj.onc.1208507

Cited by 33 publications

(25 citation statements)

References 62 publications

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“…Thus, these experiments indicated that IL-2 treatment delayed the kinetics of inactivation in NK cells when treated with the antibodies to CD16 and CD94 surface receptors. Indeed, the role of IL-2 in prevention of apoptotic cell death is clearly shown in T cells (16,18,19). However, in NK cells, it is not well established.…”

Section: Discussionmentioning

confidence: 99%

Coengagement of CD16 and CD94 Receptors Mediates Secretion of Chemokines and Induces Apoptotic Death of Naive Natural Killer Cells

Jewett

Cacalano

Head

et al. 2006

Clinical Cancer Research

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Down-modulation of CD16 (FcgRIII) receptors and loss of natural killer (NK) cell function have been observed in oral cancer patients. However, neither the mechanisms nor the significance of the decrease in CD16 receptors have been fully understood. The cytotoxic activity and survival of NK cells are negatively regulated by antibodies directed against CD16 surface receptor. The addition of anti-CD94 antibody in combination with either F(abV ) 2 fragment or intact anti-CD16 antibody to NK cells resulted in significant inhibition of NK cell cytotoxic function and induction of apoptosis in resting human peripheral blood NK cells. Addition of interleukin-2 to anti-CD16 and/or anti-CD94 antibody-treated NK cells significantly inhibited apoptosis and increased the function of NK cells. There was a significant increase in tumor necrosis factor-a (TNF-a) but not IFN-g secretion in NK cells treated either with anti-CD16 antibody alone or in combination with anti-CD94 antibodies. Consequently, the addition of anti-TNF-a antibody partially inhibited apoptosis of NK cells mediated by the combination of anti-CD94 and anti-CD16 antibodies. Increase in apoptotic death of NK cells also correlated with an increase in type 2 inflammatory cytokines and in the induction of chemokines. Thus, we conclude that binding of antibodies to CD16 and CD94 NK cell receptors induces death of the NK cells and signals for the release of chemokines.

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Section: Discussionmentioning

confidence: 99%

Coengagement of CD16 and CD94 Receptors Mediates Secretion of Chemokines and Induces Apoptotic Death of Naive Natural Killer Cells

Jewett

Cacalano

Head

et al. 2006

Clinical Cancer Research

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“…Consistent with our observation, Fung et al and Kajiyama et al showed that IL-2 induced IL-9 production in HTLV-1-infected cell lines and allergen-specific human helper T-cell clones. 35,36 Further analysis of the IL-9 promoter would be helpful to identify transcriptional elements and epigenetic events that are responsible for IL-2-induced IL-9 expression.…”

Section: Discussionmentioning

confidence: 99%

Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia

Chen

Petrus

Bryant

et al. 2010

Blood

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Interestingly, the addition of an anti-IL-2R-␣ monoclonal antibody profoundly inhibited IL-9 expression, suggesting optimal expression of IL-9 was dependent on IL-2 signaling in these patients. To determine whether there would be autonomous proliferation of ATL leukemic cells, we purified leukemic cells from patients with smoldering/chronic ATL. Purified leukemic cells cultured alone produced IL-2/ IL-9, and the downstream Janus kinase/ signal transducer and activator of transcription pathway was activated. However, the leukemic cells did not proliferate independently, but required coculture with autologous monocytes to induce proliferation. Moreover, interaction between leukemic cells and monocytes was contact dependent, and major histocompatibility complex class II expression may have contributed to this interaction. In conclusion, our data provide evidence that there is autocrine/paracrine cytokine stimulation of leukemic cell proliferation in patients with smoldering/chronic ATL that could be targeted for treatment. IntroductionAdult T-cell leukemia (ATL) that is caused by human T-cell lymphotropic virus I (HTLV-1) is an aggressive malignancy of CD4-and CD25-expressing leukemia, and lymphoma cells. ATL is a heterogeneous disease that can be divided broadly into 4 stages: smoldering, chronic, lymphoma, and acute-type ATL. The common clinical manifestations of ATL are skin lesions, hypercalcemia, immunologic anergy to antigen stimulation, and cells with "flowerlike" nuclei in the circulation. Smoldering/chronic ATL patients have normal or mildly increased white blood cell counts with a variable number of leukemic cells in the circulation and are generally associated with a better prognosis. Patients with acutetype ATL have organ dysfunction associated with circulating leukemic cells and are generally associated with a poor prognosis. The mechanisms underlying the progression from smoldering/chronic stage to the acute stage are unknown; however, the accumulation of molecular mutations is thought to play a role in this progression.Although the pathogenesis of ATL is unknown, the virally encoded regulatory protein, HTLV-1 Tax, seems to play a central role in the initial leukemogenesis of ATL. Hasegawa et al demonstrated that overexpression of Tax in immature thymocytes induced leukemia/lymphoma in mice with clinical, pathologic, and immunologic features characteristic of ATL after a long latency. 1 Subsequently, Ohsugi et al 2 showed that Tax is able to promote oncogenesis not only with immature T cells, but also with mature T cells. Both experiments highlighted the importance of Tax in the initial development of ATL.Beyond the in vivo mouse models, numerous in vitro studies have demonstrated the essential role of Tax in ATL initiation and shed light on the mechanism of Tax-mediated cellular transformation. 3 Tax deregulates the expression of genes involved in cellular proliferation, cell-cycle control, and apoptosis through physical interaction with cellular elements, including transcription factors such as nuc...

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“…HuT-102 and MT-2), this pathway may be functionally redundant since its disruption with AG-490 failed to inhibit cellular proliferation (Kirken et al, 2000). It is of interest that many genes upregulated in HTLV-transformed cells including cyclin D2 and several cytokines are IL-2 target genes and contain Stat5 binding sites in their promoters (Fung et al, 2005).…”

Section: Cytokine Receptor Signals Including Jak/statmentioning

confidence: 99%

“…The cycD2 expression is also upregulated by IL-2 receptor signals and in part accounts for the T-cell proliferation stimulated by IL-2. The IL-2 receptor induces cycD2 by activating transcription factor Stat5, which binds directly to a cognate site in the cyclin D2 promoter (Martino et al, 2001;Moon et al, 2004;Fung et al, 2005). Tax may cooperate with IL-2-signaling either indirectly through stimulating the expression of IL2Ra or directly by activating the cycD2 promoter (Huang et al, 1997;Santiago et al, 1999).…”

Section: Cyclin D Binding and Upregulationmentioning

confidence: 99%

Molecular mechanisms of cellular transformation by HTLV-1 Tax

2005

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IL-2- and STAT5-regulated cytokine gene expression in cells expressing the Tax protein of HTLV-1

Cited by 33 publications

References 62 publications

Coengagement of CD16 and CD94 Receptors Mediates Secretion of Chemokines and Induces Apoptotic Death of Naive Natural Killer Cells

Coengagement of CD16 and CD94 Receptors Mediates Secretion of Chemokines and Induces Apoptotic Death of Naive Natural Killer Cells

Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia

Molecular mechanisms of cellular transformation by HTLV-1 Tax

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