bluuebunny/crossref_metadata_2025_split huggingface dataset:
Responding naive T cells differ in their sensitivity to Fas engagement: early death of many T cells is compensated by costimulation of surviving T cells
Authors: Maksimow Mikael , Santanen Minna , Jalkanen Sirpa , Hänninen Arno 
Published: May 2003

AbstractEngagement of Fas (CD95) induces death of activated T cells but can also potentiate T-cell response to CD3 ligation. Yet, the effects of Fas-mediated signals on activation of naive T cells have remained controversial. We followed naive T cells responding under Fas ligation. Ligation of Fas simultaneously with activation by antigen-bearing dendritic cells promoted early death in half of the responding naive murine CD4 T cells. Surprisingly, it simultaneously accelerated cell division and interferon-γ (IFN-γ) production among surviving T cells. These cells developed quickly an activation-associated phenotype (CD44hi, CD62Llo), responded vigorously to antigen rechallenge, were partially resistant to subsequent induction of cell death via Fas, and were long-lived in vivo. Compared with cells becoming apoptotic, the surviving cells expressed lower levels of Fas and higher levels of T-cell receptor (TCR), CD4, and interleukin-2 receptor (IL-2R). Their survival was associated with expression of antiapoptotic cellular FLICE-inhibitory protein (c-FLIP), Bcl-XL, and Bcl-2. Thus, at the time of T-cell activation there is a subtle balance in the effects of Fas ligation that differs on a cell-to-cell basis. Factors that predict cell survival include expression levels of Fas, TCR, CD4, and IL-2R. Early death of some cells and a pronounced response of the surviving cells suggest that Fas ligation can both up- and down-regulate a primary T-cell response.
Kaposi sarcoma–associated viral cyclin K overrides cell growth inhibition mediated by oncostatin M through STAT3 inhibition
Authors: Lundquist Amy , Barré Benjamin , Bienvenu Frédéric , Hermann Jacques , Avril Sylvie , Coqueret Olivier 
Published: May 2003

AbstractDNA viruses have evolved a number of mechanisms to inhibit the major cellular tumor-suppressor pathways. Viral oncogenes can override growth suppressive signals and extend the virus proliferative capacity. The Kaposi sarsoma–associated human herpesvirus 8 (KSHV) encodes a protein, cyclin K, that is similar to cellular cyclin D1 but behaves atypically. Cyclin K resists the actions of the p16 INK4a and p27Kip1 inhibitors and extends the range of cdk6 substrates, thereby inducing cell-cycle progression toward S phase. In this study, we show that cyclin K overrides growth suppressive signals through signal transducer and activator of transcription 3 (STAT3) inactivation. Cyclin K was found to associate with the activation domain of STAT3 to inhibit its DNA-binding and transcriptional activities. Overexpression of cyclin K and inhibition of STAT3 prevents the growth suppressive effect imposed by the interleukin 6–type cytokine, oncostatin M. Altogether, these results suggest that KSHV is able to override growth suppressive effects through multiple mechanisms, and they further indicate that cyclin K plays an important role in the oncogenic activity of these viruses.
Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency
Authors: Bovenschen Niels , Herz Joachim , Grimbergen Jos M. , Lenting Peter J. , Havekes Louis M. , Mertens Koen , van Vlijmen Bart J. M. 
Published: May 2003

AbstractIt has been established that low-density lipoprotein receptor-related protein (LRP) is involved in the cellular uptake and degradation of coagulation factor VIII (FVIII) in vitro. To address the physiologic role of LRP in regulating plasma FVIII in vivo, we used cre/loxP–mediated conditional LRP- deficient mice (MX1cre+LRPflox/flox). Upon inactivation of the LRP gene, MX1cre+LRPflox/flox mice had significantly higher plasma FVIII as compared with control LRPflox/floxmice (3.4 and 2.0 U/mL, respectively; P < .001). Elevated plasma FVIII levels in MX1cre+LRPflox/flox mice coincided with increased plasma von Willebrand factor (VWF) (2.0 and 1.6 U/mL for MX1cre+LRPflox/flox and control LRPflox/flox mice, respectively; P < .05). Elevation of plasma FVIII and VWF persisted for at least 6 weeks after inactivation of the LRP gene. Upon comparing plasma FVIII and VWF in individual mice, we observed an increase of the FVIII/VWF ratio in MX1cre+LRPflox/flox mice as compared with control LRPflox/flox mice. Administration of either a vasopressin analog or an endotoxin resulted in increased plasma VWF, but not FVIII. In clearance experiments, MX1cre+LRPflox/flox mice displayed a 1.5-fold prolongation of FVIII mean residence time. Adenovirus-mediated overexpression of the 39-kDa receptor–associated protein (RAP) in normal mice resulted in a 3.5-fold increase of plasma FVIII. These data confirm that the regulation of plasma FVIII in vivo involves a RAP-sensitive mechanism. Surprisingly, plasma FVIII in MX1cre+LRPflox/flox mice increased 2-fold after RAP gene transfer. We propose that RAP-sensitive determinants other than hepatic LRP contribute to the regulation of plasma FVIII in vivo.
A defect in hematopoietic stem cell migration explains the nonrandom X-chromosome inactivation in carriers of Wiskott-Aldrich syndrome
Authors: Lacout Catherine , Haddad Elie , Sabri Siham , Svinarchouk Fedor , Garçon Loic , Capron Claude , Foudi Adlen , Mzali Rym , Snapper Scott B. , Louache Fawzia , Vainchenker William , Duménil Dominique 
Published: May 2003

AbstractA defect in cell trafficking and chemotaxis plays an important role in the immune deficiency observed in Wiskott-Aldrich syndrome (WAS). In this report, we show that marrow cells from WAS protein (WASP)–deficient mice also have a defect in chemotaxis. Serial transplantation and competitive reconstitution experiments demonstrated that marrow cells, including hematopoietic progenitors and stem cells (HSCs), have decreased homing capacities that were associated with a defect in adhesion to collagen. During development, HSCs migrate from the liver to the marrow and the spleen, prompting us to ask if a defect in HSC homing during development may explain the skewed X-chromosome inactivation in WAS carriers. Preliminary evidence has shown that, in contrast to marrow progenitor cells, fetal liver progenitor cells from heterozygous females had a random X-chromosome inactivation. When fetal liver cells from WASP-carrier females were injected into irradiated recipients, a nonrandom inactivation of the X-chromosome was found at the level of hematopoietic progenitors and HSCs responsible for the short- and long-term hematopoietic reconstitution. Therefore, the mechanism of the skewed X-chromosomal inactivation observed in WAS carriers may be related to a migration defect of WASP-deficient HSCs.
Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells
Authors: Panther Elisabeth , Corinti Silvia , Idzko Marco , Herouy Yared , Napp Matthias , la Sala Andrea , Girolomoni Giampiero , Norgauer Johannes 
Published: May 2003

AbstractDendritic cells (DCs) express functional purinergic type 1 receptors, but the effects of adenosine in these antigen-presenting cells have been only marginally investigated. Here, we further characterized the biologic activity of adenosine in immature DCs (iDCs) and lipopolysaccharide (LPS)–matured DCs (mDCs). Chronic stimulation with adenosine enhanced the macropinocytotic activity and the membrane expression of CD80, CD86, major histocompatibility complex (MHC) class I, and HLA-DR molecules on iDCs. Adenosine also increased LPS-induced CD54, CD80, MHC class I, and HLA-DR molecule expression in mDCs. In addition, adenosine dose-dependently inhibited tumor necrosis factor α and interleukin-12 (IL-12) release, whereas it enhanced the secretion of IL-10 from mDCs. The use of selective receptor agonists revealed that the modulation of the cytokine and cell-surface marker profile was due to activation of A2 adenosine receptor. Functionally, adenosine reduced the allostimulatory capacity of iDCs, but not of mDCs. More important, DCs matured in the presence of adenosine had a reduced capacity to induce T helper 1 (Th1) polarization of naive CD4+ T lymphocytes. Finally, adenosine augmented the release of the chemokine CCL17 and inhibited CXCL10 production by mDCs. In aggregate, the results provide initial evidence that adenosine diminishes the capacity of DCs to initiate and amplify Th1 immune responses.
Reciprocal effects of C/EBPα and PKCδ on JunB expression and monocytic differentiation depend upon the C/EBPα basic region
Authors: Liu Huaitian , Keefer Jeffrey R. , Wang Qian-fei , Friedman Alan D. 
Published: May 2003

AbstractMonocytic differentiation of 32DPKCδ cells in response to activation of protein kinase C δ (PKCδ) by phorbol 12-myristate 13-acetate (PMA) was inhibited by exogenous CCAAT/enhancer binding protein α–estradiol receptor (C/EBPα-ER), which impeded morphologic maturation and induction of macrosialin mRNA. Inhibition of monopoiesis was also evident in 32DPKCδ subclones expressing C/EBPαLeu12Val-ER, which cannot dimerize or bind DNA because of mutation of the leucine zipper, C/EBPαGZ-ER, in which the leucine zipper has been replaced by the GCN4 zipper, or C/EBPαΔ3-8-ER, lacking the C/EBPα transactivation domains. In contrast, C/EBPαBR3-ER, containing a mutant basic region, did not inhibit monocytic differentiation. C/EBPα-ER strongly inhibited endogenous AP-1 DNA-binding. Supershift analysis revealed that the major AP-1 complex contains JunB. Activation of C/EBPα-ER specifically reduced endogenous JunB RNA and protein and exogenous JunB levels without affecting endogenous or exogenous c-Jun. The stability of PMA-induced JunB was not affected. Thus, C/EBPα-ER suppresses both JunB transcription and posttranscriptional protein generation or induction. PU.1 levels and activity were increased. The Leu12Val, GZ, and Δ3-8 mutants also inhibited JunB expression, whereas the BR3 mutant was ineffective, indicating that inhibition of JunB expression and monocytic differentiation by C/EBPα-ER depends upon an interaction mediated by its basic region. Exogenous JunB restored AP-1 DNA-binding but did not prevent inhibition of macrosialin expression by C/EBPα-ER, indicating that JunB is not the only target relevant to inhibition of monopoiesis by C/EBPα.
Nephrotic syndrome with crescent formation and massive IgA deposition following allogeneic bone marrow transplantation for natural killer cell leukemia/lymphoma
Authors: Kimura Shinya , Horie Akeyo , Hiki Yoshiyuki , Yamamoto Chie , Suzuki Satoru , Kuroda Junya , Deguchi Masayo , Kato Gen-ichi , Karasuno Takahiro , Hiraoka Akira , Yoshikawa Toshikazu , Maekawa Taira 
Published: May 2003

Abstract
We describe herein a case of nephrotic syndrome (NS) following allogeneic bone marrow transplantation (allo-BMT) for natural killer cell leukemia/lymphoma. Histologic studies defined the diagnosis as crescentic glomerulonephritis with massive immunoglobulin A (IgA) deposition, which has never been reported in NS cases following allo-BMT. Most of the massive infiltrated cells in the interstice were CD3+CD4−CD8+ T cells derived from the donor. We observed mesangial deposition of Haemophilus parainfluenza outer membrane (OMHP) antigen and decreased glycosylation of the IgA1 hinge in the recipient's samples is consistent with the recently reported pathogenesis of IgA nephropathy. Further, the titer of IgA antibody against the donor serum was as high as other IgA nephropathy cases. These findings suggest that NS and crescentic glomerulonephritis in this case occurred as one of the forms of chronic graft-versus-host disease (GVHD), and that IgA deposition was associated with H parainfluenza and decreased glycosylation of the IgA1 hinge.
Regulation of tissue factor and inflammatory mediators by Egr-1 in a mouse endotoxemia model
Authors: Pawlinski Rafal , Pedersen Brian , Kehrle Bettina , Aird William C. , Frank Rolf D. , Guha Mausumee , Mackman Nigel 
Published: May 2003

AbstractIn septic shock, tissue factor (TF) activates blood coagulation, and cytokines and chemokines orchestrate an inflammatory response. In this study, the role of Egr-1 in lipopolysaccharide (LPS) induction of TF and inflammatory mediators in vivo was evaluated using Egr-1+/+ and Egr-1−/− mice. Administration of LPS transiently increased the steady-state levels of Egr-1 mRNA in the kidneys and lungs of Egr-1+/+ mice with maximal induction at one hour. Egr-1 was expressed in epithelial cells in the kidneys and lungs in untreated and LPS-treated mice. LPS induction of monocyte chemoattractant protein mRNA in the kidneys and lungs of Egr-1−/− mice was not affected at 3 hours, but its expression was significantly reduced at 8 hours compared with the expression observed in Egr-1+/+ mice. Similarly, LPS induction of TF mRNA expression in the kidneys and lungs at 8 hours was reduced in Egr-1−/− mice. However, Egr-1 deficiency did not affect plasma levels of tumor necrosis factor α in endotoxemic mice. Moreover, Egr-1+/+ and Egr-1−/− mice exhibited similar survival times in a model of acute endotoxemia. These data indicate that Egr-1 does not contribute to the early inflammatory response in the kidneys and lungs or the early systemic inflammatory response in endotoxemic mice. However, Egr-1 does contribute to the sustained expression of inflammatory mediators and to the maximal expression of TF at 8 hours in the kidneys and lungs.
G-protein–coupled receptor signaling in Syk-deficient neutrophils and mast cells
Authors: Mócsai Attila , Zhang Hong , Jakus Zoltán , Kitaura Jiro , Kawakami Toshiaki , Lowell Clifford A. 
Published: May 2003

AbstractThe Syk tyrosine kinase is essential for immunoreceptor and multiple integrin functions as well as being implicated in signaling from G-protein–coupled receptors (GPCR) in cell lines, transfection systems, and pharmacologic studies. In contrast, using Syk-deficient primary cells, we show here that Syk does not play a major functional role in chemoattractant/chemokine signaling in neutrophils and mast cells. syk−/− neutrophils showed normal respiratory burst and degranulation in response to the bacterial peptide formyl-Met-Leu-Phe (fMLP). The migration of neutrophils toward fMLP was similarly not affected by the syk−/−mutation. fMLP initiated normal Ca2+-signal, activation of the extracellular signal-related kinase (ERK) and p38 mitogen–activated protein (MAP) kinase cascades, and polymerization of cellular actin in the absence of Syk.syk−/− and wild-type neutrophils also responded similarly to LTB4, C5a, and the chemokines macrophage inflammatory protein-1 (MIP-1)α or MIP-2, both in functional assays and in intracellular signaling mechanisms. Furthermore, bone marrow–derived syk−/− mast cells showed normal activation of the Akt, ERK, and p38 MAP kinase pathways when stimulated by the GPCR ligand adenosine. We conclude that, in contrast to previous reports, Syk does not play a major role in GPCR signaling.
Effects of combined chelation treatment with pyridoxal isonicotinoyl hydrazone analogs and deferoxamine in hypertransfused rats and in iron-loaded rat heart cells
Authors: Link Gabriela , Ponka Prem , Konijn Abraham M. , Breuer William , Cabantchik Z. Ioav , Hershko Chaim 
Published: May 2003

Abstract
Although iron chelation therapy with deferoxamine (DFO) results in improved life expectancy of patients with thalassemia, compliance with parenteral DFO treatment is unsatisfactory, underlining the need for alternative drugs and innovative ways of drug administration. We examined the chelating potential of pyridoxal isonicotinoyl hydrazone (PIH) analogs, alone or in combination with DFO, using hypertansfused rats with labeled hepatocellular iron stores and cultured iron-loaded rat heart cells. Our in vivo studies using 2 representative PIH analogs, 108-o and 109-o, have shown that PIH analogs given orally are 2.6 to 2.8 times more effective in mobilizing hepatocellular iron in rats, on a weight-per-weight basis, than parenteral DFO administered intraperitoneally. The combined effect of DFO and 108-o on hepatocellular iron excretion was additive, and response at a dose range of 25 to 200 mg/kg was linear. In vitro studies in heart cells showed that DFO was more effective in heart cell iron mobilization than all PIH analogs studied. Response to joint chelation with DFO and PIH analogs was similar to an increase in the equivalent molar dose of DFO alone, rather than the sum of the separate effects of the PIH analog and DFO. This finding was most likely the result of iron transfer from PIH analogs to DFO, a conclusion supported directly by iron-shuttle experiments using fluorescent DFO. These findings provide a rationale for the combined, simultaneous use of iron-chelating drugs and may have useful, practical implications for designing novel strategies of iron chelation therapy.
Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment
Authors: Relling Mary V. , Boyett James M. , Blanco Javier G. , Raimondi Susana , Behm Frederick G. , Sandlund John T. , Rivera Gaston K. , Kun Larry E. , Evans William E. , Pui Ching-Hon 
Published: May 2003

Abstract
Event-free survival for children with acute lymphoblastic leukemia (ALL) now exceeds 80% in the most effective trials. Failures are due to relapse, toxicity, and second cancers such as therapy-related myeloid leukemia or myelodysplasia (t-ML). Topoisomerase II inhibitors and alkylators can induce t-ML; additional risk factors for t-ML remain poorly defined. The occurrence of t-ML among children who had received granulocyte colony-stimulating factor (G-CSF) following ALL remission induction therapy prompted us to examine this and other putative risk factors for t-ML in 412 children treated on 2 consecutive ALL protocols from 1991 to 1998. All children received etoposide and anthracyclines, 99 of whom received G-CSF; 284 also received cyclophosphamide, 58 of whom also received cranial irradiation. There were 20 children who developed t-ML at a median of 2.3 years (range, 1.0-6.0 years), including 16 cases of acute myeloid leukemia, 3 myelodysplasia, and 1 chronic myeloid leukemia. Stratifying by protocol, the cumulative incidence functions differed (P = .017) according to the use of G-CSF and irradiation: 6-year cumulative incidence (standard error) of t-ML of 12.3% (5.3%) among the 44 children who received irradiation without G-CSF, 11.0% (3.5%) among the 85 children who received G-CSF but no irradiation, 7.1% (7.2%) among the 14 children who received irradiation plus G-CSF, and 2.7% (1.3%) among the 269 children who received neither irradiation nor G-CSF. Even when children receiving irradiation were excluded, the incidence was still higher in those receiving G-CSF (P = .019). In the setting of intensive antileukemic therapy, short-term use of G-CSF may increase the risk of t-ML.
Cytokine-mediated regulation of iron transport in human monocytic cells
Authors: Ludwiczek Susanne , Aigner Elmar , Theurl Igor , Weiss Günter 
Published: May 2003

AbstractUnder chronic inflammatory conditions cytokines induce a diversion of iron traffic, leading to hypoferremia and retention of the metal within the reticuloendothelial system. However, the regulatory pathways underlying these disturbances of iron homeostasis are poorly understood. We investigated transferrin receptor (TfR)–dependent and –independent iron transport mechanisms in cytokine-stimulated human monocytic cell lines THP-1 and U937. Combined treatment of cells with interferon-γ (IFN-γ) and lipopolysaccharide (LPS) reduced TfR mRNA levels, surface expression, and iron uptake, and these effects were reversed by interleukin-10 (IL-10), thus stimulating TfR-mediated iron acquisition. IFN-γ and LPS dose-dependently increased the cellular expression of divalent metal transporter-1, a transmembrane transporter of ferrous iron, and stimulated the uptake of nontransferrin bound iron (NTBI) into cells. At the same time, IFN-γ and LPS down-regulated the expression of ferroportin mRNA, a putative iron exporter, and decreased iron release from monocytes. Preincubation with IL-10 partly counteracted these effects. Our results demonstrate that the proinflammatory stimuli IFN-γ and LPS increase the uptake of NTBI via stimulation of divalent metal transporter-1 expression and cause retention of the metal within monocytes by down-regulating ferroportin synthesis. Opposite, the anti-inflammatory cytokine IL-10 stimulates TfR-mediated iron uptake into activated monocytes. The regulation of iron transport by cytokines is a key mechanism in the pathogenesis of anemia of chronic disease and a promising target for therapeutic intervention.
Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia
Authors: Shen LanLan , Toyota Minoru , Kondo Yutaka , Obata Toshiro , Daniel Sophia , Pierce Sherry , Imai Kohzoh , Kantarjian Hagop M. , Issa Jean-Pierre J. , Garcia-Manero Guillermo 
Published: May 2003

Abstract
P57KIP2 is a cyclin-dependent kinase inhibitor silenced in a variety of human malignancies. DNA methylation of a region surrounding the transcription start site of p57KIP2 was found in acute lymphocytic leukemia (ALL)–derived cell lines. Methylation of this region correlated with gene silencing, and treatment of methylated/silenced cell lines with 5-aza-2′-deoxycytidine resulted in gene re-expression. P57KIP2 was methylated in 31 (50%) of 63 patients with newly diagnosed ALL, and in 11 (52%) of 21 patients with relapsed ALL. In 5 of them (25%), methylation was acquired at relapse. No association was observed between methylation of p57KIP2 alone and clinical-biologic characteristics studied, including overall survival (OS) or disease-free survival. Methylation of multiple genes in a cell-cycle regulatory pathway composed of p73, p15, and p57KIP2 occurred in 22% of Philadelphia chromosome (Ph)–negative patients. Ph-negative patients with methylation of 2 or 3 genes of this pathway had a significantly worse median OS compared with those with methylation of 0 or 1 gene (50 vs 467 weeks, respectively;P = .02). Our results indicate that p57KIP2 is frequently methylated in adult patients with ALL, and that inactivation of a pathway composed of p73, p15, and p57KIP2 predicts for poor prognosis in Ph-negative patients.