bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Regulation of Lipopolysaccharide (LPS) Activation Pathways in Mouse Macrophages by LPS-Binding Proteins
Authors: Amura Claudia R. , Kamei Takayuki , Ito Noriko , Soares Michael J. , Morrison David C. 
Published: December 2022

AbstractLPS binding to its receptor(s) on macrophages induces the synthesis of inflammatory mediators involved in septic shock. While the signaling mechanism(s) remains to be fully defined, the human LPS-binding protein (LBP) is known to regulate responses to LPS by facilitating its binding to CD14 on human monocytes. The structurally related bactericidal permeability increasing protein (BPI) differs from LBP by inhibiting LPS-induced human monocyte activation. We have demonstrated that, unlike the human monocyte response to LPS, both LBP and BPI inhibited LPS-stimulated TNF-α production in mouse peritoneal macrophages. In contrast, LPS-dependent nitric oxide release was not affected by LBP. LPS induces the phosphorylation of a number of proteins in a dose and time-dependent manner, however, the pattern of LPS-induced phosporylation was not reduced by either LBP or BPI under conditions that result in selective TNF-α inhibition. Further, activation of the transcription factor NF-κB in response to LPS was also not modified by either LBP or BPI. Finally, no differences were detected in TNF-α or inducible nitric oxide synthase mRNA accumulations induced by LPS in the presence or absence of either protein, whereas a slight decreased mRNA stability was observed in the group with LPS treatment. These results would suggest that many of the early signaling events contribute to LPS-induced macrophage signaling at a point preceding the divergence of pathways that differentially regulate TNF-α and NO production.
The Up-Regulation of IL-6 and IL-8 in Human Endothelial Cells by Activated Protein C
Authors: Hooper W. Craig , Phillips Donald J. , Renshaw Mary A. , Evatt Bruce L. , Benson Jane M. 
Published: December 2022

AbstractThe protein C/protein S anticoagulant pathway has been proposed to be a common link between coagulation and inflammation. Studies have suggested that a component of the anticoagulant pathway, activated protein C (APC), may play a role in the inflammatory response by modulating the effects of cytokines such as TNF and by blocking neutrophil activation. Cytokines are known to be intimately involved in the inflammatory response and to function in part to restore hemostatic balance. To begin to delineate what role APC may have in the inflammatory response, we have investigated the effect of APC on the production of the proinflammatory cytokines IL-6 and IL-8 in primary HUVEC, human microvascular endothelial cells, and human coronary artery endothelial cells. Our results have demonstrated that physiologic concentrations of APC significantly up-regulated the production of both IL-6 and IL-8. This increase, which was seen at both the RNA and protein level, was not due to either thrombin or LPS contamination of the APC preparation. Additional studies also showed that the APC-mediated up-regulation of IL-6 and IL-8 was IL-1 independent. Although neither purified protein C nor protein S alone had an effect on cytokine production, protein S, the cofactor for APC, significantly enhanced the ability of APC to up-regulate IL-6/IL-8 production. These results provide further evidence for a role for APC in the inflammatory response.
The Heat Shock Response Inhibits RANTES Gene Expression in Cultured Human Lung Epithelium
Authors: Ayad Onsy , Stark James M. , Fiedler Michael M. , Menendez Ingrid Y. , Ryan Marnie A. , Wong Hector R. 
Published: December 2022

AbstractThe chemokine RANTES is thought to be involved in the pathophysiology of inflammation-associated acute lung injury. Although much is known regarding signals that induce RANTES gene expression, relatively few data exist regarding signals that inhibit RANTES gene expression. The heat shock response, a highly conserved cellular defense mechanism, has been demonstrated to inhibit a variety of lung proinflammatory responses. We tested the hypothesis that induction of the heat shock response inhibits RANTES gene expression. Treatment of A549 cells with TNF-α induced RANTES gene expression in a concentration-dependent manner. Induction of the heat shock response inhibited subsequent TNF-α-mediated RANTES mRNA expression and secretion of immunoreactive RANTES. Transient transfection assays involving a RANTES promoter-luciferase reporter plasmid demonstrated that the heat shock response inhibited TNF-α-mediated activation of the RANTES promoter. Inhibition of NF-κB nuclear translocation with isohelenin inhibited TNF-α-mediated RANTES mRNA expression, indicating that RANTES gene expression is NF-κB dependent in A549 cells. Induction of the heat shock response inhibited degradation of the NF-κB inhibitory protein, I-κBα but did not significantly inhibit phosphorylation of I-κBα. We conclude that the heat shock response inhibits RANTES gene expression by a mechanism involving inhibition of NF-κB nuclear translocation and subsequent inhibition of RANTES promoter activation. The mechanism by which the heat shock response inhibits NF-κB nuclear translocation involves stabilization of I-κBα, without significantly affecting phosphorylation of I-κBα.
Increased Susceptibility to Postoperative Sepsis in Patients with Impaired Monocyte IL-12 Production
Authors: Hensler Thorsten , Heidecke Claus-Dieter , Hecker Heike , Heeg Klaus , Bartels Holger , Zantl Niko , Wagner Hermann , Siewert Jörg-Rüdiger , Holzmann Bernhard 
Published: December 2022

AbstractIL-12 is a potent immunoregulatory cytokine that is essential for the development of protective immunity, as demonstrated by numerous animal models of infection. Here, we provide evidence for a critical role of IL-12 in human sepsis. The results of a prospective study of 184 patients undergoing major elective surgery of the upper and lower gastrointestinal tract revealed that, in contrast to patients showing uneventful recovery, monocyte IL-12 production was severely and selectively impaired in patients developing postoperative sepsis. Moreover, the extent of monocyte IL-12 suppression correlated with the severity of postoperative sepsis. Monocyte IL-12 secretion was suppressed before surgery and remained low until the onset of sepsis. Therefore, the suppression of IL-12 secretion preceded the onset of postoperative sepsis but did not occur as a consequence of major surgery. In contrast, IL-1β production was only reduced during the late postoperative course in patients developing postoperative sepsis, and TNF-α release was even increased at different time intervals before the onset of sepsis. Thus, reduced IL-12 release does not reflect a general defect in monocyte cytokine production. Consequently, these results establish a critical role for IL-12 in early resistance to postoperative infection and may allow for the development of novel therapeutic strategies designed to stimulate host defense mechanisms and to reduce the incidence and severity of septic complications.
Prostaglandin E2 and Dexamethasone Inhibit IL-12 Receptor Expression and IL-12 Responsiveness
Authors: Wu Chang-You , Wang Kening , McDyer John F. , Seder Robert A. 
Published: December 2022

AbstractRegulation of the factors governing IL-12R expression and IL-12 responsiveness has been shown to be important in the generation and stability of Th1- and Th2-type responses. In this regard, cytokines have been shown to have a prominent role in regulating IL-12R expression. In this study, the role that PGE2 and dexamethasone (DXM) have in regulating IL-12R expression was evaluated. Addition of PGE2 or DXM to human PBMCs stimulated with immobilized anti-CD3 plus IL-12 inhibited the production of IFN-γ in a dose-responsive manner. Moreover, PBMCs stimulated with immobilized anti-CD3 in the presence of PGE2 or DXM for 3 days, washed extensively, and restimulated in the presence of IL-12 still did not produce IFN-γ. This lack of IL-12 responsiveness from cells cultured in either PGE2 or DXM was correlated with diminished surface expression of IL-12Rβ1, IL-12Rβ2 mRNA expression, and IL-12 binding. Finally, the PGE2- and DXM-mediated inhibition of IL-12R expression was not affected significantly by addition of neutralizing Abs against either IL-4, IL-10, or TGF-β. By contrast, addition of dibutyryl cAMP, 8-bromoadenosine 3:5 cAMP (8-Br-cAMP), or cholera toxin substantially reduced IL-12R expression, suggesting that PGE2 may be mediating its effects through enhancement of cAMP.
The Susceptibility of Mice to Immune-Mediated Neurologic Disease Correlates with the Degree to Which Their Lymphocytes Resist the Effects of Brain-Derived Gangliosides
Authors: Irani David N. 
Published: December 2022

AbstractSJL mice develop immune-mediated disorders of the central nervous system (CNS) when infected with certain neurotropic viruses or when immunized with myelin Ags. Other strains including BALB/c are more resistant to these diseases. During Sindbis virus-induced encephalitis, both mice are easily infected and elicit rapid mononuclear cell inflammation in the brain. However, only SJL mice develop immune-mediated paralysis; BALB/c mice remain asymptomatic. To understand how the same stimulus produces such divergent immunologic effects on the host, the present study investigated lymphocytes that were isolated from the brains of Sindbis virus-infected animals. Cells from the brains of SJL mice exhibited more proliferation, produced more IL-2, maintained a higher viability, and expressed less bax mRNA (a proapoptotic mediator) than did lymphocytes from the brains of BALB/c mice. Since the central nervous system is enriched in gangliosides that regulate T cell proliferation and IL-2 production in vitro, purified brain-derived gangliosides were tested on peripheral lymphocytes from both strains. These lipids had less of an effect on the mitogen-induced proliferation, IL-2 production, activation-induced cell death, and up-regulation of bax mRNA in lymphocytes from SJL mice compared with those from BALB/c mice. Thus, gangliosides may inhibit various T cell effector functions and induce T cell apoptosis to a greater degree in the brains of BALB/c mice compared with the brains of SJL mice. This relative deficiency in local lymphocyte regulation may enhance the susceptibility of SJL mice to immune-mediated neurologic disease.
Granzymes D, E, F, and G Are Regulated Through Pregnancy and by IL-2 and IL-15 in Granulated Metrial Gland Cells
Authors: Allen Melissa P. , Nilsen-Hamilton Marit 
Published: December 2022

AbstractGranulated metrial gland (GMG) cells are NK cells that proliferate and differentiate within the murine uterus during pregnancy. They have been predicted to play important roles in nurturing the embryo, normal placentation, and uterine tissue remodeling. GMG cell differentiation is manifested by the accumulation of the cytolytic mediators, perforin, granzyme A, and granzyme B, within cytoplasmic granules. The signaling mechanisms required for GMG cell differentiation are largely unknown, although recent in vitro assays have implicated IL-15 in these events. In this report, we demonstrate that granzymes D, E, F, and G (granzymes D–G) are also expressed in GMG cells but at a later stage in pregnancy when compared with granzyme A expression. Whereas granzyme A is expressed in early to mid-gestation, the expression of granzymes D–G peak in mid- to late gestation. In addition, we show that the expression patterns of IL-2Rβ and the IL-2Rγ mRNAs overlap with that of granzyme D–G mRNAs in the pregnant uterus. Finally, we demonstrate that granzymes D–G are up-regulated by IL-2 and IL-15 in primary cultures containing GMG cells. Taken together, these results suggest that IL-2 and/or IL-15 may regulate GMG cell differentiation in vivo, and that granzymes D–G may have different functions than granzyme A during pregnancy.
Prostaglandin E2 Induces the Final Maturation of IL-12-Deficient CD1a+CD83+ Dendritic Cells: The Levels of IL-12 Are Determined During the Final Dendritic Cell Maturation and Are Resistant to Further Modulation
Authors: Kaliński Paweł , Schuitemaker Joost H. N. , Hilkens Catharien M. U. , Kapsenberg Martien L. 
Published: December 2022

AbstractActivation of immature dendritic cells (DC) in peripheral tissues induces their migration to lymph nodes and their maturation into CD83+ DC, which are able to prime naive T cells. The inflammatory cytokines IL-1β and TNF-α induce mature DC, which can secrete IL-12 and promote the development of Th0/Th1-biased cells. DC maturation factors with a Th2-promoting function have not been described. Here we show that PGE2, although it does not induce final DC maturation by itself, synergizes with IL-1β and TNF-α, and allows their effectiveness at 100-fold lower concentrations. While being phenotypically identical with the DC matured in the presence of high concentrations of IL-1β and TNF-α alone, DC matured in the additional presence of PGE2 show impaired IL-12 production and bias naive Th cell development toward the Th2. The ability of DC to produce IL-12 is also suppressed by IL-10, which in contrast to PGE2, inhibits their maturation. The differences in the ability to produce IL-12, established during the final DC maturation, are stable after the removal of modulatory factors. Importantly, fully mature DC become unsusceptible to PGE2 and IL-10. This indicates that the levels of IL-12 production in vivo, in mature DC interacting with Th cells within the lymph nodes, are mainly predetermined at the stage of immature DC in peripheral tissues. These data imply that the character of pathogen-induced local inflammatory reaction can “instruct” local DC to initiate Th1 or Th2-biased responses.
Molecular Modeling of an Anti-DNA Autoantibody (V-88) and Mapping of Its V Region Epitopes Recognized by Heterologous and Autoimmune Antibodies
Authors: Hobby Paul , Ward Francis J. , Denbury Andrew N. , Williams D. Gwyn , Staines Norman A. , Sutton Brian J. 
Published: December 2022

Abstract
Anti-DNA autoantibodies are a characteristic feature of human systemic lupus erythematosus (SLE) and lupus diseases in the mouse. V-88 is an IgG1/κ ssDNA-binding Ab, derived from a lupus mouse, that bears a cross-species, cross-reactive Id (CRI) that has been implicated in the pathogenesis of both human and murine disease. A linear epitope map of V-88 has been determined with anti-idiotypic antisera obtained from rabbits, and candidate sequences for the idiotopes of the CRI have been proposed. We now report the modeling of the three-dimensional structure of the V regions of Ab V-88, to map the location of these idiotopes. The V region framework structure was derived from those of crystallographically determined Ab structures, and the complementarity determining region (CDR) structures were based upon the set of canonical structures adopted by these loop regions in Abs of known structure. One of the idiotopes is an extensive, highly accessible epitope consisting of framework regions spatially adjacent to CDR2 in the heavy chain. Epitopes recognized by an anti-idiotypic rabbit antiserum were compared with those recognized by autoimmune sera from SLE-prone mice, and common features were identified. By analogy with the crystal structure of an anti-DNA Ab BV04-01 complexed with a trinucleotide, the modeled structure also suggests a mode of binding of ssDNA to V-88. The location of the candidate CRI, although within the framework region of VH, is such that it could influence Ag specificity.
Human T Cell Leukemia Virus-I (HTLV-I) Tax-Mediated Apoptosis in Activated T Cells Requires an Enhanced Intracellular Prooxidant State
Authors: Los Marek , Khazaie Khashayarsha , Schulze-Osthoff Klaus , Baeuerle Patrick A. , Schirrmacher Volker , Chlichlia Katerina 
Published: December 2022

Abstract
We have shown that an estradiol-dependent activation of human T cell leukemia virus-I Tax leads to the inhibition of cell proliferation and to the induction of apoptosis. The present study demonstrates that a hormone-dependent activation of Tax promotes an enhanced prooxidant state in stably transfected Jurkat cells as measured by changes in the intracellular levels of glutathione and H2O2; these changes are followed by apoptotic cell death. Additional stimulation of the CD3/TCR pathway enhances the oxidative and apoptotic effects. Both Tax-mediated apoptosis and oxidative stress can be potently suppressed by antioxidants, as is seen with the administration of recombinant thioredoxin (adult T cell leukemia-derived factor) or pyrrolidine dithiocarbamate. Hormone-induced Tax activation induces a long-lasting activation of NF-κB, which is a major target of reactive oxygen intermediates. The long-term exposure of Jurkat cells to hormone eventually results in a selection of cell clones that have lost Tax activity. A subsequent transfection of these apparently “nonresponsive” clones allows the recovery of Tax responses in these cells. Our observations indicate that changes in the intracellular redox status may be a determining factor in Tax-mediated DNA damage, apoptosis, and selection against the long-term expression of Tax function.
Treatment ofParacoccidioides brasiliensis-Infected Mice with a Nitric Oxide Inhibitor Prevents the Failure of Cell-Mediated Immune Response
Authors: Bocca Anamélia L. , Hayashi Emília E. , Pinheiro Artur G. , Furlanetto Alessandra B. , Campanelli Ana P. , Cunha Fernando Q. , Figueiredo Florêncio 
Published: December 2022

AbstractThe activation of the nitric oxide (NO) production system and its involvement in the control of the lung fungal burden and in immunosuppression mechanisms were studied during the course of Paracoccidioides brasiliensis-infected mice. Mice that had been infected with the fungus were treated daily with a specific inhibitor of NO synthesis, Nω-nitro-l-arginine, or with buffered saline (control); NO production was assessed on the basis of spontaneous NO2− production by bronchoalveolar and peritoneal macrophages (Mφ) and of serum NO3− levels. The infection coursed with an elevation of NO3− levels. The Mφ produced NO2− and released TNF-α only after stimulation with LPS. In addition, the immunoproliferative responses of spleen cells that had been stimulated with the fungus Ag or with Con A were depressed. An examination of the lungs of infected animals showed a progressive increase in the size of the lesions. Treatment of the animals, which resulted in an inhibition of NO2− production by Mφ and a reduction of serum NO3− levels, caused the spontaneous release of TNF-α from infected animals and prevented the failure of the lymphoproliferative capacity of spleen cells. Furthermore, the treatment resulted in less pulmonary damage despite the fact that the lung fungal burden increased. It was also demonstrated that the NO donors S-nitroso-acetyl penicillamine and 3-morpholino-sydnonimine-hydrochloride were able to inhibit the growth of P. brasiliensis in vitro. These results suggest that although NO is important for the killing of the fungi, the activation of NO production in P. brasiliensis infection contributes to the occurrence of the immunosuppression observed during the course of the infection.
Tissue and T Cell Distribution of Precursor and Mature IL-16
Authors: Chupp Geoffrey L. , Wright Eric A. , Wu David , Vallen-Mashikian Margaret , Cruikshank William W. , Center David M. , Kornfeld Hardy , Berman Jeffrey S. 
Published: December 2022

AbstractIL-16 is a novel cytokine, which is chemoattractant for CD4+ T cells, macrophages, and eosinophils. Recently, it was reported that IL-16 is synthesized as an approximately 80-kDa precursor molecule, pro-IL-16. Since little is known about the processing and tissue distribution of IL-16 and pro-IL-16, we investigated the distribution of IL-16 mRNA and protein in human lymphoid tissue. Northern blotting identified IL-16 mRNA predominantly in normal lymphoid organs, including PBMC, spleen, and thymus. Immunohistochemistry of human lymph node localized IL-16 protein to lymphocyte cytoplasm within T cell zones and occasionally in lymphocytes in B cell zones. Flow cytometric detection of intracellular IL-16 showed that &gt;70% of CD4+ and CD8+ T cells constitutively expressed IL-16 protein. Western blot analysis of PBMC revealed nearly all of this protein to be approximately 80-kDa pro-IL-16 in unstimulated PBMC, and upon cell activation, the amino terminus of pro-IL-16 is processed into multiple fragments. These results show that pro-IL-16 is widely and constitutively expressed and suggest that the amino terminus of the protein can be processed upon cell activation.
TNFR80-Dependent Enhancement of TNFR60-Induced Cell Death Is Mediated by TNFR-Associated Factor 2 and Is Specific for TNFR60
Authors: Weiss Tilo , Grell Matthias , Siemienski Katrin , Mühlenbeck Frank , Dürkop Horst , Pfizenmaier Klaus , Scheurich Peter , Wajant Harald 
Published: December 2022

Abstract
Costimulation of TNFR80 can strongly enhance TNFR60-induced cell death. In this study, we show that this enhancement is TNFR60 selective, as neither TNF-related apoptosis-inducing ligand/Apo2 ligand-, Apo1/Fas-, ceramide-, nor daunorubicin-mediated cell death was affected by costimulation of TNFR80. We further demonstrate that TNFR-associated factor 2 (TRAF2) is critically involved in both negative and positive regulation of TNF-induced cell death. Overexpression of TRAF2 and of a TRAF2 mutant, deficient in nuclear factor-κB activation, selectively desensitized and enhanced, respectively, TNFR60-induced cell death in HeLa cells. However, upon costimulation of TNFR80, which mediates activation of nuclear factor-κB and the c-Jun amino-terminal kinase via TRAF2, TNF-induced cell death is drastically enhanced in parental and TRAF2-transfected, but not in TRAF2 (87–501)-transfected cells. These data point to a critical role of TRAF2 in the apoptotic TNFR cross talk, whereby the TNFR80-dependent enhancement of TNFR60-induced cell death is due to TNFR80-mediated negative regulation of TRAF2 function(s). An interference with TRAF2 function was confirmed independently by analysis of c-Jun amino-terminal kinase activation via TNFR60 upon prestimulation of TNFR80. We propose that the apoptotic TNFR cross talk is based on TNFR80-mediated abrogation of antiapoptotic TRAF2-dependent signaling pathways initiated by TNFR60, but not Apo1/Fas or the apoptotic TNF-related apoptosis-inducing ligand receptors.
Functional Analysis of Peripheral Blood B Cells in Patients with X-Linked Agammaglobulinemia
Authors: Nonoyama Shigeaki , Tsukada Satoshi , Yamadori Tomoki , Miyawaki Toshio , Jin Yin Zhu , Watanabe Chiaki , Morio Tomohiro , Yata Jun-Ichi , Ochs Hans D. 
Published: December 2022

AbstractX-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations of Bruton tyrosine kinase (Btk); Btk plays an essential role in the development of mature B cells. However, small numbers of B cells (“leaky B cells”) are present in the peripheral blood of most XLA patients. In this study, we analyzed the function of these leaky B cells obtained from XLA patients. Enough numbers of B cells were available for analysis from five of nine XLA patients originally screened. Sequence analysis revealed missense mutations of Btk in four of the five XLA patients. No mutation was found in the coding region of Btk in one patient. Western blotting and/or flow cytometric analysis failed to detect Btk protein in all five patients. B cells isolated from peripheral blood of these XLA patients were CD5−, CD20+, CD19+, and CD21−. If stimulated with anti-CD40 and IL-4, XLA B cells proliferated normally and produced significant amounts of IgE. Anti-CD40 stimulation of XLA B cells resulted in normal expression of CD23. In addition, three of the five XLA patients studied were immunized with bacteriophage φX174 and produced low but detectable levels of antiphage-specific Ab. Similarly, X-linked immunodeficiency mice, which carry a missense mutation in Btk, produced substantial amounts of antiphage Ab. These results indicate that CD40 signaling is intact in B cells lacking demonstrable Btk, and that leaky B cells in XLA patients can proliferate, undergo isotype switching, and differentiate into specific Ab-producing cells.