IL‐2 withdrawal induces HTLV‐1 expression through p38 activation in ATL cell lines

Washiyama, Miki; Nishigaki, Kazuo; Ahmed, Nursarat; Kinpara, Syuichi; Ishii, Yuichi; Kanzawa, Noriyuki; Masuda, Tohru; Kannagi, Mari

doi:10.1016/j.febslet.2007.10.008

Cited by 10 publications

(9 citation statements)

References 13 publications

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“…The HTLV-1 mRNA level in ILT-Hod cells cultured in the absence of IL-2 was significantly higher than that in the cells cultured with IL-2, in agreement with our previous report (33). Nevertheless, the HTLV-1 expression in ILT-Hod cells injected into WT mice was significantly lower than that in control ILT-Hod cells.…”

Section: Suppression Of Htlv-1 Expression By Mefs From Wt But Not Irf-7supporting

confidence: 79%

“…To detect intracellular HTLV-1 antigens, cells were fixed and permeabilized as described previously (33) and serially stained with anti-HTLV-1 p19 mouse monoclonal antibody GIN-7 (29) or control ascites and fluorescein isothiocyanate (FITC)-conjugated goat anti-mouse immunoglobulin G (IgG) plus IgM (IgGϩIgM) antibodies. The stained cells were analyzed by using a flow cytometer (FACSCalibur; Becton Dickinson, San Jose, CA).…”

Section: Cellsmentioning

confidence: 99%

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Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon

Kinpara

Hasegawa

Utsunomiya

et al. 2009

J Virol

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Section: Suppression Of Htlv-1 Expression By Mefs From Wt But Not Irf-7supporting

confidence: 79%

Section: Cellsmentioning

confidence: 99%

Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon

Kinpara

Hasegawa

Utsunomiya

et al. 2009

J Virol

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“…26 Although the mechanism whereby Tax is up-regulated in short-term cultures of HAM/TSP PBMCs has yet to be fully characterized, the activation of stress kinases such as p38 mitogen-activated protein kinase after cytokine withdrawal, and the subsequent cAMP response element-binding protein activation, may explain HTLV-I viral gene expression in culture. 27 Thus, local environmental cues may contribute to induction of Tax expression and ultimately to NF-B activation in the HTLV-Iinfected cells of HAM/TSP. NF-B activation was a causal influence on lymphocyte activation in HAM/TSP.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of immune activation by a novel nuclear factor-kappa B inhibitor in HTLV-I–associated neurologic disease

McCormick

Datta

et al. 2011

Blood

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The human T-lymphotropic virus type I (HTLV-I IntroductionInfection with the retrovirus human T-lymphotropic virus type I (HTLV-I) is associated with the development of HTLV-Iassociated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). HAM/TSP is an immune-mediated inflammatory disorder of the central nervous system that leads to progressive neurologic disability in affected individuals. 1 A key mechanism in the pathogenesis of HAM/TSP is considered to be the HTLV-I-induced immune activation that supports the establishment of central nervous system inflammation. 2 Immune activation is a hallmark of HAM/TSP, as evidenced by the increased expression of lymphocyte activation markers, the induction of pro-inflammatory cytokines, and spontaneous lymphoproliferation. [3][4][5] The HTLV-I-encoded transactivating protein Tax is thought to play a role in the immune activation associated with HAM/TSP by activating hostsignaling molecules such as the cyclic AMP-responsive elementbinding protein, the serum response factor, and the nuclear factor-B (NF-B), thereby up-regulating the expression of pro-inflammatory cytokines and/or their receptors. 6 The activation of the NF-B pathway is considered a key event in the HTLV-I-induced leukemogenesis leading to ATLL, 7 but the contribution of the NF-B pathway to the pathogenesis of HAM/TSP has not been fully defined.The NF-B proteins, which include the RelA (p65), c-Rel, RelB, NF-B1 (p105/p50), and NF-B2 (100/p52) subunits, comprise a family of Rel-homology domain-containing transcription factors that play a key role in regulating inflammation. 8 NF-B signaling occurs by activation of either the canonical or the noncanonical pathways, leading to nuclear translocation of the RelA/p50 or RelB/p52 heterodimers, respectively. 9 Key signaling events involve the release of NF-B subunits from the cytoplasmic sequestration by the inhibitor of NF-B (IB), the subsequent nuclear translocation, and the binding of NF-B heterodimers to NF-B response elements that ultimately lead to gene transcription. The HTLV-I protein Tax is capable of activating both the canonical and the noncanonical NF-B pathways by interacting with the IB kinase subunits, leading to the release of NF-B from cytoplasmic sequestration. 10,11 The NF-B-dependent induction of pro-inflammatory cytokines such as [13][14][15]14 and the induction of IL-2 receptor␣ (IL-2R␣) 15 in HTLV-I-infected cells suggests that NF-B activation may play a critical role in the development of diseases associated with HTLV-I infection.To further define the contribution of NF-B activation to the pathogenesis of HAM/TSP, we compared NF-B 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-B activation. We developed several series of novel inhibitor of NF-B targeting the DNA-binding Rel transcription factors. [16][17][18] To define the contribution of NF-B activation to immune...

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“…This study used IL-2-dependent ILT-Hod cells derived from chronic ATL patient (17). HUT102 cell line, which has the capacity for IL-2-independent cell growth, was also used (1).…”

Section: Cellsmentioning

confidence: 99%

JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

Yamada

Ozaki

Akiyama

et al. 2012

Molecular Cancer Therapeutics

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Adult T-cell leukemia (ATL) is a heterogeneous tumor that is resistant to chemotherapy. Telomerase activity plays a critical role in tumorigenesis and is associated with the prognosis of ATL patients. Interleukin (IL)-2 commonly promotes tumor growth in chronic ATL cells. The signaling pathways involved in IL-2-regulated telomerase activation were studied in ATL cells derived from chronic ATL patients. IL-2 challenge enhanced tyrosine phosphorylation of Janus-activated kinase (JAK)1-3 and STAT5, and induced JAK1 and JAK2 to associate with STAT5 in IL-2-dependent ATL cells. Chromatin immunoprecipitation assays revealed that STAT5 directly bound to the human telomerase reverse transcriptase (hTERT) promoter. STAT5 short interfering RNA inhibited hTERT transcription in IL-2-stimulated ATL cells. Inhibitors of PI3K, HSP90, and mTOR reduced IL-2-induced hTERT mRNA, protein expression, and telomerase activity. AKT, HSP90, mTOR, S6 kinase, and hTERT immunoprecipitate from IL-2-stimulated cells contained telomerase activity, suggesting that hTERT directly interacts with, and is regulated by, these proteins. Binding of the p85 regulatory subunit of PI3K to JAK2 was enhanced in an IL-2-dependent manner, indicating that JAK2 propagates activation signals from the IL-2 receptor and links hTERT activation to both the STAT5 and PI3K pathways. Finally, IL-2-induced activation of telomerase and STAT5 was observed in primary leukemic cells. These results indicate that IL-2 stimulation induces hTERT activation through the JAK/STAT pathway and the JAK/PI3K/AKT/HSP90/ mTORC1 pathway in IL-2-responsive ATL cells. These signaling proteins represent novel and promising molecular therapeutic targets for IL-2-dependent ATL.

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IL‐2 withdrawal induces HTLV‐1 expression through p38 activation in ATL cell lines

Cited by 10 publications

References 13 publications

Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon

Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon

Inhibition of immune activation by a novel nuclear factor-kappa B inhibitor in HTLV-I–associated neurologic disease

JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

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