Frequent expression of interleukin-9 mRNA and infrequent involvement of interleukin-9 in proliferation of primary adult T-cell leukemia cells and HTLV-I infected T-cell lines

Matsushita, Kakushi; Arima, Naomichi; Ohtsubo, Hideo; Fujiwara, Hiroshi; Hidaka, Shiroh; Fukumori, Junko; Tanaka, Hiromitsu

doi:10.1016/s0145-2126(96)00109-9

Cited by 21 publications

(15 citation statements)

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“…In addition, IL-9R␣ expression has not been detected on ATL cells and the weak response of ex vivo, primary ATL cells to exogenous IL-9 further obscures the potential role of IL-9 in ATL disease. 21,22 Here we show that IL-9 expression is associated with the expression of HTLV-I Tax protein in primary ATL cells. Conversely, the expression of IL-9R␣ does not appear to be induced by Tax.…”

Section: Introductionmentioning

confidence: 67%

“…21 In addition, after the cloning and characterization of human, genomic IL-9, it was speculated that HTLV-I Tax might transactivate IL-9 expression in light of the presence of a putative NF-B binding site in the proximal IL-9 promoter. 20 However, the observation that IL-9 mRNA expression did not correlate with Tax expression in HTLV-I-infected cell lines did not support this speculation.…”

Section: Discussionmentioning

confidence: 99%

“…20 However, the observation that IL-9 mRNA expression did not correlate with Tax expression in HTLV-I-infected cell lines did not support this speculation. 21 Moreover, the dramatic induction of IL-9 mRNA expression after IL-2 addition in the HTLV-I-infected, IL-2-dependent cell line, T1, raised the possibility that HTLV-I Tax protein alone was not sufficient for the induction of IL-9 expression. 38 Here we present data that demonstrate that in the ex vivo cultured ATL cell Tax expression is associated with the transactivation of IL-9.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 However, the understanding of IL-9/IL-9R in the context of HTLV-I infection and ATL is incomplete. A number of studies have shown that IL-9 expression is increased by HTLV-I infection, and transcripts for IL-9 are readily detected in many HTLV-I-infected cell lines and primary ATL cells 20,21 ; however, the mechanism of this activation has not been fully explored. In addition, IL-9R␣ expression has not been detected on ATL cells and the weak response of ex vivo, primary ATL cells to exogenous IL-9 further obscures the potential role of IL-9 in ATL disease.…”

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confidence: 99%

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Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism

Chen

Petrus

Bryant

et al. 2008

Blood

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The etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type I (HTLV-I). The HTLV-I proteinTax 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-B motif in its proximal promoter, whereas IL-9 receptor-␣ (IL-9R␣) expression is not induced by Tax. However, supporting a role for IL-9/IL-9R␣ in ATL, a neutralizing monoclonal antibody directed toward IL-9R␣ 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-9R␣ 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-9R␣/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. (Blood. 2008; 111:5163-5172) IntroductionAdult T-cell leukemia (ATL) is a highly aggressive neoplasm characterized by a clonal expansion of CD4 ϩ lymphocytes and by a monoclonal integration of human T cell lymphotropic virus type I (HTLV-I) provirus(es) in the tumor cells. 1,2 HTLV-I is a type C retrovirus endemic in southern Japan, the Caribbean basin, Central and Southern Africa, and South America. 3,4 Less than 5% of HTLV-I-infected persons develop either ATL or a chronic inflammatory disease of the central nervous system termed HTLV-Iassociated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the precise mechanisms of ATL leukemogenesis remain unclear, it has been suggested that the transformation of T cells in the early stages of the disease is mediated by the HTLV-I Tax protein (p40). Tax activates long terminal repeat-directed transcription by recruiting members of the cAMP response element-binding/ and activating transcription factors family to the viral promoter. In addition, Tax activates other cellular transcription factors, such as NF-B. Tax is associated with the expression of cellular genes, 5 including the cytokine 6-10 and cytokine receptor genes. 7,[11][12][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 Interleukin-9 (IL-9) is a T cell-derived cytokine with pleiotropic activities on various cell types. 14-16 IL-9 is mainly expressed by activated CD4 ϩ T cells. 17 The functions of IL-9 are mediated through the IL-9 receptor (IL-9R), which is a member of the hematopoietin receptor superfamily. 18 The IL-9 recept...

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Section: Introductionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism

Chen

Petrus

Bryant

et al. 2008

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). In addition, previous studies have suggested that IL-13 is a growth factor in Hodgkin's lymphoma (Skinnider et al, 2001;Skinnider et al, 2002) and the observation that IL-13 is produced by HTLV-1-infected cells (Ruckes et al, 2001;Chung et al, 2003;Waldele et al, 2004) has led to the hypothesis that IL-13 might contribute to the growth of ATL cells.…”

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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Poor response to prednisolone of idiopathic thrombocytopenia with human T‐lymphotropic virus type I infection

et al. 2002

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We describe the unique clinical characteristics of patients with idiopathic thrombocytopenic purpura (ITP) who are infected by human T-lymphotropic virus type I (HTLV-I).Thirty-seven patients with ITP were examined in the present study: 10 patients had HTLV-I infection, and the remaining 27 did not. The mean age of the group with HTLV-I infection was significantly older than that of the group without infection (

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Frequent expression of interleukin-9 mRNA and infrequent involvement of interleukin-9 in proliferation of primary adult T-cell leukemia cells and HTLV-I infected T-cell lines

Cited by 21 publications

References 17 publications

Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism

Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism

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

Poor response to prednisolone of idiopathic thrombocytopenia with human T‐lymphotropic virus type I infection

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