Eosinophilia associated with adult t-cell leukemia: Role of interleukin 5 and granulocyte-macrophage colony-stimulating factor

Ogata, Masao; Ogata, Yuko; Kohno, Kazuhiro; Uno, Noritaka; Ohno, Eiji; Ohtsuka, Eiichi; Saburi, Yoshio; Kamberi, Perparim; Nasu, Masaru; Kojima, Hiroshi

doi:10.1002/(sici)1096-8652(199811)59:3<242::aid-ajh11>3.0.co;2-o

Cited by 25 publications

(8 citation statements)

References 19 publications

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“…The expression of a wide array of T-cell associated cytokines, including those characteristic of different T-helper cell subtypes has also been seen in both ATL cells and HTLV-1-transformed human cells, and a number of these cytokines have been shown to be directly regulated by Tax, including IL-5, IL-10, IL-13, and GM-CSF. 23,[33][34][35] The relative amounts of Tax mRNA expression do not always directly correlate with the amounts of these cytokines secreted over the time course of cell growth. The complexity of cytokine regulation, involving both transcriptional and posttranscriptional events may obscure such a direct correlation.…”

Section: Discussionmentioning

confidence: 99%

Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells

Swaims¹,

Khani

Zhang³

et al. 2010

Blood

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Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/ lymphoma (ATL). IntroductionHuman T-cell Leukemia Virus-1 (HTLV-1) is a CD4 ϩ T cell-tropic human deltaretrovirus infecting 10-20 million people worldwide. 1,2 HTLV-1 was the first human retrovirus isolated and is the causative agent of diverse diseases such as Adult T-cell Leukemia/ Lymphoma (ATL), a fatal CD4 ϩ T-cell Leukemia/Lymphoma and HTLV-1 Acquired Myelopathy/Tropical Spastic Paraparesis (HAM-TSP), a demyelinating disease of the spinal cord. Approximately 3%-5% of those infected with HTLV-1 will develop disease, while the majority of carriers remain asymptomatic. Development of HAM/TSP or ATL occurs after long clinically latent periods and specific disease phenotypes tend to be associated with particular routes and timing of infection. 3 The mechanisms responsible for HTLV-1 pathogenesis remain poorly understood.Development of HTLV-1-associated diseases is dependent upon expression of HTLV-1 gene products, most notably the HTLV-1 viral transcriptional transactivator, Tax 4 and other regulatory proteins including the HBZ protein. 5,6 Tax expression is required for viral replication, and can induce CD4 ϩ T-cell immortalization. Tax enhances viral gene expression through interactions with cellular transcription factors at the HTLV-1 Long Terminal Repeat (LTR) promoter. Tax also interacts with many host proteins involved in cell survival, proliferation, genomic stability, and cell cycle regulation to promote altered cellular gene expression. 4 Thus, Tax plays a critical role in regulating viral gene expression, as well as the host cellular response to infection. Recently, HBZ has also been shown to play an important role in HTLV-1 pathogenesis both through increased viral load, and enhancing T-cell proliferation in culture and transgenic mice. 7,8 p12 I , an activator of STAT5 antiapoptotic signaling is also likely to play a role in HTLV-1 transformation. 9 Determining the cellular and viral events that regulate HTLV-1 gene expression is central to understanding pathogenesis of HTLV-1 infection. Our laboratory has previously shown that Tax expression in chronically infected human CD4 ϩ T cells can be markedly enhanced by immune activation stimuli, such as PMA, PHA, or anti-CD3 antibody. 10,11 These data suggest that immune stimulation of infected cells, through T-cell antigen receptor signaling, could regulate a balance of virus-host interactions leading to increased viral gene expression.To elucidate whether immune activation events contribute to HTLV-1-associated-diseases, study of animal models of pathogenesis will be valuable. Although mouse models of Tax-associated oncogenesis have been described, 12-14 a transgenic model of Tax-derived CD4 ϩ T-cell oncogenesis, reflecting regulation of Tax by the authentic HTLV-1 LTR has yet to be established. Transgenic mice expressing Tax under the control of the LTR, are phenotypically normal until approximately 3 months of age, when they deve...

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Section: Discussionmentioning

confidence: 99%

Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells

Swaims¹,

Khani

Zhang³

et al. 2010

Blood

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“…For instance, eosinophilia is seen in a significant percentage of patients with ATL (Murata et al, 1992) and IL-5 has been proposed to be involved in this phenotype in at least some cases (Yamagata et al, 1997;Ogata et al, 1998). IL-9 has been shown to be a growth factor for murine and human T cells (Uyttenhove et al, 1988;Houssiau et al, 1993) and it is produced by many HTLV-1-infected cell lines (Matsushita et al, 1997;Chung et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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Interleukin-2 (IL-2) mediates cell cycle progression and antiapoptosis in human T cells via several signal transduction pathways. The Tax protein of the human T-cell leukemia virus type I (HTLV-1) deregulates cell growth and alters the role of IL-2 in infected cells. However, Tax-immortalized cells stay dependent on IL-2, suggesting that events besides HTLV-1 gene expression are required for leukemia to develop. Here, IL-2-dependent and -independent events were analysed in a human T cell line immortalized by Tax. These studies show that, of the signaling pathways evaluated, only STAT5 remains dependent. Microarray analyses revealed several genes, including il-5, il-9 and il-13, are uniquely upregulated by IL-2 in the presence of Tax. Bioinformatics and supporting molecular biology show that some of these genes are STAT5 targets, explaining their IL-2 upregulation. These results suggest that IL-2 and viral proteins work together to induce gene expression, promoting the hypothesis that deregulation via the constitutive activation of STAT5 may lead to the IL-2-independent phenotype of HTLV-1-transformed cells.

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“…For example, ATL cell-produced IL-5 caused eosinophilia, and granulocyte-monocyte colony-stimulating factor increased the number of neutrophils. 34 Monocytosis is one of the clinical features of ATL, in which increased M-CSF should be implicated in the pathogenesis. 35 M-CSF increased precursor cells, which supports the differentiation into monocytes and OCLs.…”

Section: Pathologic Role Of Ranklmentioning

confidence: 99%

Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor κB ligand on adult T-cell leukemia cells

Nosaka

Miyamoto

Sakai

et al. 2002

Blood

156

118

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Hypercalcemia is one of the most frequent and serious complications in patients with adult T-cell leukemia (ATL) and is due to marked bone resorption by accumulation of osteoclasts (OCLs). Although several cytokines such as interleukin 1 and parathyroid hormone-related protein are thought to be involved in the development of high serum Ca ؉؉ levels, its precise underlying mechanism remains unknown. This study analyzed the expression of various genes that are thought to regulate serum Ca ؉؉ levels in ATL and showed that the overexpression of the receptor activator of nuclear factor

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Eosinophilia associated with adult t-cell leukemia: Role of interleukin 5 and granulocyte-macrophage colony-stimulating factor

Cited by 25 publications

References 19 publications

Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells

Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells

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

Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor κB ligand on adult T-cell leukemia cells

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