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Jacobus, PA, United States

Nguyen V.-P.,U.S. National Institutes of Health | Chen J.,U.S. National Institutes of Health | Petrus M.N.,U.S. National Institutes of Health | Goldman C.K.,U.S. National Institutes of Health | And 3 more authors.
Journal of Innate Immunity | Year: 2014

Toll/IL-1R domain-containing adaptor inducing interferon-β (IFN-β) factor (TRIF) is a key adaptor for Toll-like receptor (TLR) 3 and TLR4 signaling. Using a novel cDNA isolate encoding a TRIF protein with a 21-residue deletion (Δ160-181) from its amino-terminal half, we investigated the impact of this deletion on TRIF functions. Transfection studies consistently showed higher expression levels of the (Δ160-181) TRIF compared to wild-type (wt) TRIF, an effect unrelated to apoptosis, cell lines or plasmid amplification. Colocalization of wt and (Δ160-181) TRIF proteins led to a dramatic reduction of their respective expressions, suggesting that wt/(Δ160-181) TRIF heterocomplexes are targeted for degradation. We demonstrated that wt TRIF associates with tumor necrosis factor-α receptor-associated factor 3 (TRAF3) better than (Δ160-181) TRIF, culminating in its greater ubiquitination and proteolysis. This explains, in part, the differential expression levels of the two TRIF proteins. Despite higher expression levels in transfected cells, (Δ160-181) TRIF inefficiently transactivated the IFN pathway, whereas the nuclear factor-κB (NF-κB) pathway activation remained similar to that by wt TRIF. In coexpression studies, (Δ160-181) TRIF marginally contributed to the IFN pathway activation, but still enhanced NF-κB signaling with wt TRIF. Therefore, this 21 amino acid sequence is crucial for TRAF3 association, modulation of TRIF stability and activation of the IFN pathway. © 2014 S. Karger AG, Basel. Source

Yu P.,U.S. National Cancer Institute | Petrus M.N.,U.S. National Cancer Institute | Ju W.,U.S. National Cancer Institute | Zhang M.,U.S. National Cancer Institute | And 6 more authors.
Leukemia | Year: 2015

Adult T-cell leukemia (ATL) is an aggressive malignancy caused by human T-cell lymphotropic virus-1. There is no accepted curative therapy for ATL. We have reported that certain ATL patients have increased Notch-1 signaling along with constitutive activation of the nuclear factor-κB pathway. Physical and functional interaction between these two pathways provides the rationale to combine the γ-secretase inhibitor compound E with the proteasome inhibitor bortezomib. Moreover, romidepsin, a histone deacetylase inhibitor, has demonstrated major antitumor action in leukemia/lymphoma. In this study, we investigated the therapeutic efficacy of the single agents and the combination of these agents in a murine model of human ATL, the MT-1 model. Single and double agents inhibited tumor growth as monitored by tumor size (P<0.05), and prolonged survival of leukemia-bearing mice (P<0.05) compared with the control group. The combination of three agents significantly enhanced the antitumor efficacy as assessed by tumor size, tumor markers in the serum (human soluble interleukin-2 receptor-α and β2-microglobulin) and survival of the MT-1 tumor-bearing mice, compared with all other treatment groups (P<0.05). Improved therapeutic efficacy obtained by combining compound E, bortezomib and romidepsin supports a clinical trial of this combination in the treatment of ATL. © 2015 Macmillan Publishers Limited. All rights reserved. Source

Yu P.,U.S. National Cancer Institute | Bamford R.N.,Transponics | Waldmann T.A.,U.S. National Cancer Institute
European Journal of Immunology | Year: 2014

Interleukin-15 (IL-15) is an inflammatory cytokine whose role in autoimmune diseases has not been fully elucidated. Th17 cells have been shown to play critical roles in experimental autoimmune encephalomyelitis (EAE) models. In this study, we demonstrate that blockade of IL-15 signaling by TMβ-1 mAb treatment aggravated EAE severity. The key mechanism was not NK-cell depletion but depletion of CD8+CD122+ T cells. Adoptive transfer of exogenous CD8+CD122+ T cells to TMβ-1-treated mice rescued animals from severe disease. Moreover, transfer of preactivated CD8+CD122+ T cells prevented EAE development and significantly reduced IL-17 secretion. Naïve effector CD4+CD25- T cells cultured with either CD8+CD122+ T cells from wild-type mice or IL-15 transgenic mice displayed lower frequencies of IL-17A production with lower amounts of IL-17 in the supernatants when compared with production by effector CD4+CD25- T cells cultured alone. Addition of a neutralizing antibody to IL-10 led to recovery of IL-17A production in Th17 cultures. Furthermore, coculture of CD8+CD122+ T cells with effector CD4+ T cells inhibited their proliferation significantly, suggesting a regulatory function for IL-15 dependent CD8+CD122+ T cells. Taken together, these observations suggest that IL-15, acting through CD8+CD122+ T cells, has a negative regulatory role in reducing IL-17 production and Th17-mediated EAE inflammation. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Chen J.,U.S. National Cancer Institute | Petrus M.,U.S. National Cancer Institute | Bamford R.,Transponics | Shih J.H.,U.S. National Cancer Institute | And 3 more authors.
Blood | Year: 2012

Large granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disease of mature T and natural killer cells. The etiology of LGL leukemia is unknown. IL-15 is an inflammatory cytokine that stimulates T and natural killer cells and is critical for their survival and proliferation. IL-15 signals through a heterotrimeric receptor that is composed of a private receptor, IL-15Rα and IL-2/IL-15Rβ and γ c shared with IL-2. Using a newly developed assay, we demonstrated increased levels of soluble IL-15Rα in the serum of patients with T-LGL leukemia. Furthermore, IL-15Rα mRNA levels were also up-regulated in the PBMCs of these patients. FACS analysis indicated that IL-15Rα was expressed both on monocytes as well as on some CD8 + leukemic cells of the patients. Interestingly, themRNA levels of IFN-α, a known inducer of IL-15Rα, were also up-regulated in patients' PBMCs. Moreover, PBMCs of some T-LGL patients proliferated at higher levels in response to exogenously added IL-15 compared with those of normal donors. In summary, our study demonstrated increased expression of IL-15Rα in T-LGL leukemia. It is conceivable that higher IL-15Rα expression may lower IL-15 response threshold in vivo and, therefore, may contribute to the pathogenesis of the disease. Source

Sato N.,U.S. National Cancer Institute | Sabzevari H.,U.S. National Cancer Institute | Fu S.,U.S. National Cancer Institute | Ju W.,U.S. National Cancer Institute | And 4 more authors.
Blood | Year: 2011

IL-15 has growth-promoting effects on select lymphoid subsets, including natural killer (NK) cells, NK T cells, intraepithelial lymphocytes (IELs), CD8 T cells, and γδ-T cells. Constitutive expression of murine IL-15 in IL-15-transgenic mice was reported to cause T-NK leukemia. We investigated whether IL-15 expression is sufficient for leukemic transformation using a human IL-15-transgenic (IL-15Tg) mouse model. We noted that 100% of the mice observed over a 2-year period (n > 150) developed fatal expansions of CD8 T cells with NK markers, and determined that these cells expressed IL-15 receptor alpha (IL-15Rα). The expression of IL-15Rα on CD8 T cells appears to be required for uncontrolled aggressive lymphoproliferation, because none of the IL-15Rα -/--IL-15Tg mice that we followed for more than 2 years developed the fatal disease despite controlled expansion of CD8 T cells. In addition, in contrast to IL-15Tg mice, in which leukemia-like CD8 T cells expressed IL-15Rα persistently, acutely activated normal CD8 T cells only transiently expressed IL-15Rα. Inhibition of DNA methylation enabled sustained IL-15Riv expression induced by activation. We present a scenario for IL-15Tg mice in which CD8 T cells that acquire constitutive persistent IL-15Rα expression are at a selective advantage and become founder cells, outgrow other lymphocytes, and lead to the establishment of a leukemia-like condition. Copyright 2011 by The American Society of Hematology; all rights reserved. Source

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