Exaggerated Messenger RNA Expression of Inflammatory Cytokines in Human T-Cell Lymphotropic Virus Type I--Associated Myelopathy

Watanabe, Hiroko; Nakamura, Tatsufumi; Nagasato, Kunihiko; Shirabe, Susumu; Ohishi, Kiyosumi; Ichinose, Katsuhiro; Nishiura, Yoshihiro; Chiyoda, Shin; Tsujihata, Mitsuhiro; Nagataki, Shigenobu

doi:10.1001/archneur.1995.00540270068021

Cited by 26 publications

(6 citation statements)

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“…21 STAT proteins function to mediate cytokine signal transduction, such that the detection of STAT activation can be used as an indicator of cytokine production and signaling. 22 We analyzed the activation of STAT5 protein to examine the induction of cytokines in PBMCs from subjects with HAM/TSP.…”

Section: Inhibition Of Nf-b Leads To Modulation Of Immune Activation mentioning

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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Section: Inhibition Of Nf-b Leads To Modulation Of Immune Activation mentioning

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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“…It has been reported that CD4+ cells in HAM/TSP patients deviate to Th1-like phenotype as characterized by upregulated secretion of proinflammatory cytokines such as IFN-g, TNF-a, and IL-2 and downregulation of Th 2 cytokines such as IL-4 (Watanabe et al 1995; Nakamura et al 2000; Horiuchi et al 2000; Hanon et al 2001; Goon et al 2003). Th1 cells but not Th2 cells are reported to bind to P- and E-selectin expressed on endothelial cells (Austrup et al 1997).…”

Section: Htlv-i Infected Cd4+ Cell and Its Migration To Extracellularmentioning

confidence: 99%

Neuroimmunity of HTLV-I Infection

Matsuura

Yamano

Jacobson

2010

J Neuroimmune Pharmacol

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Human T-lymphotrophic virus type I (HTLV-I) is an oncogenic retrovirus and its infection is associated with a variety of human diseases including HTLV-I-associated myelopathy/tropic spastic paraparesis (HAM/TSP). Large numbers of epidemiological, virological, immunological, and clinical studies on HTLV-I- and HTLV-I-associated diseases have been published, although the pathogenesis of HAM/TSP remains to be fully understood. In the last several years, researchers have shown that several key factors are important in HTLV-I-associated neurologic disease including high HTLV-I proviral load and a strong immune response to HTLV-I. Here, we review pathophysiological findings on HAM/TSP and focus on viral-host immune responses to the virus in HTLV-I infected individuals. In particular, the role of HTLV-I-specific CD8+ T cell response is highlighted.

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“…In addition, the HTLV-I provirus load may influence cytokine production, because HTLV-I-infected cells possibly produce greater amounts of cytokines, compared with uninfected cells, through the transactivational activity of Tax on cytokine genes. However, previous studies have not made it clear whether the higher production of these cytokine mRNA in the PBMCs of patients with HAM/TSP versus ACs is simply caused by the higher HTLV-I provirus load or whether the cytokine expression in individual Tax-expressing cells is higher in patients with HAM/ TSP [11]. In addition, previous results regarding the cytokine production were obtained in the supernatant of PBMCs after 3-4 days of culture, and it was not determined whether this high cytokine production was produced in HTLV-I -infected cells themselves [12].…”

mentioning

confidence: 96%

“…However, there are ACs with a high HTLV-I provirus load [8]; therefore, we wanted to determine whether there were factors other than HTLV-I provirus load that would influence the outcome of HTLV-I infection. Second, the production of inflammatory cytokines, such as interferon (IFN)-g and tumor necrosis factor (TNF)-a have been examined in patients with HAM/TSP [11][12][13], and an immunocytochemical study revealed overexpression of IFN-g and TNF-a by infiltrating lymphocytes in the central nervous system (CNS) of patients with HAM/TSP [14]. It also has been reported that the adhesion of lymphocytes to cultured cerebral endothelium was increased by IFN-g and/or TNF-a [15].…”

mentioning

confidence: 99%

“…Furthermore, IFN-g induces major histocompatibility complex (MHC) class II antigens [16] and might elicit a T cell-mediated immune response leading to CNS damage [17], and inflammatory cytokines were postulated to play a role in the pathogenesis of HAM/TSP [18]. Expression of these cytokine genes, as determined by reverse-transcriptase polymerase chain reaction (RT-PCR), is detected more frequently in patients with HAM/TSP than in ACs or seronegative control subjects [11]. An increased production of these cytokines in patients with HAM/TSP was reported in the supernatant of cultured PBMCs, compared with that in uninfected healthy control subjects, as described elsewhere [12].…”

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confidence: 99%

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Different Cytokine Production in Tax‐Expressing Cells between Patients with Human T Cell Lymphotropic Virus Type I (HTLV‐I)–Associated Myelopathy/Tropical Spastic Paraparesis and Asymptomatic HTLV‐I Carriers

Furukawa¹,

Saito²,

Matsumoto³

et al. 2003

J INFECT DIS

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Exaggerated Messenger RNA Expression of Inflammatory Cytokines in Human T-Cell Lymphotropic Virus Type I--Associated Myelopathy

Cited by 26 publications

References 35 publications

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

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

Neuroimmunity of HTLV-I Infection

Different Cytokine Production in Tax‐Expressing Cells between Patients with Human T Cell Lymphotropic Virus Type I (HTLV‐I)–Associated Myelopathy/Tropical Spastic Paraparesis and Asymptomatic HTLV‐I Carriers

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