bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Role of IL-15 in the Development of Osteoclasts: Inability to Replace Its Activity with IL-2
Authors: Ogata Yoshiyasu , Kukita Akiko , Kukita Toshio , Komine Mitunori , Miyahara Akira , Miyazaki Sumio , Kohashi Osamu 
Published: December 2022

AbstractIL-15 shares many activities with IL-2 on stimulating lymphocytes, hematopoietic progenitor cells, and macrophages. However, the role of IL-15 in osteoclastogenesis has not been elucidated. The recent finding of abundant IL-15 in rheumatoid arthritis synovial fluids suggested a possible role for this cytokine in the pathological destruction of bone and prompted us to determine whether IL-15 stimulates osteoclast formation. IL-15 stimulated the formation of multinucleated osteoclast-like cells in rat bone marrow cultures. In stroma-free cultures, IL-15 increased the number of mononuclear preosteoclast-like cells in the early stage of osteoclast formation. The stimulation was observed even after treatment with IL-15 for only 24 or 48 h of culture. Moreover, low IL-15 concentration (0.1 ng/ml) strongly increased the level of calcitonin receptor mRNA of mononuclear preosteoclast-like cells. Although IL-15 is known as a potent stimulator of TNF-α, its activity was not abolished by addition of anti-TNF-α Ab. Interestingly, IL-2 and IL-7, which utilize some IL-15R components, had no effect on osteoclast differentiation, but pretreatment with IL-2 or IL-7 of bone marrow cells before the addition of IL-15 inhibited the enhancing activity of IL-15. In summary, IL-15 has a novel activity to stimulate the differentiation of osteoclast progenitors into preosteoclasts, which cannot be replaced by IL-2 but may use components in common with IL-2R to mediate its effects.
A Tailless Fas-FADD Death-Effector Domain Chimera Is Sufficient to Execute Fas Function in T Cells But Not B Cells of MRL-lpr/lprMice
Authors: Kabra Nisha H. , Cado Dragana , Winoto Astar 
Published: December 2022

AbstractThe Fas receptor delivers signals crucial for lymphocyte apoptosis through its cytoplasmic death domain. Several Fas cytoplasmic-associated proteins have been reported and studied in cell lines. So far, only Fas-associated death domain protein (FADD), another death domain-containing molecule has been shown to be essential for Fas signals in vivo. FADD is thought to function by recruiting caspase-8 through its death-effector domain. To test whether FADD is sufficient to deliver Fas signals, we generated transgenic mice expressing a chimera comprised of the Fas extracellular domain and FADD death-effector domain. Expression of this protein in lymphocytes of Fas-deficient MRL-lpr/lpr mice completely diminishes their T cell but not their B cell abnormalities. These results suggest that FADD alone is sufficient for initiation of Fas signaling in primary T cells, but other pathways may operate in B cells.
Role of Innate and Adaptive Immunity in the Outcome of Primary Infection withChlamydia pneumoniae, as Analyzed in Genetically Modified Mice
Authors: Rottenberg Martín E. , Gigliotti Rothfuchs Antonio C. , Gigliotti Dulceaydee , Svanholm Cecilia , Bandholtz Lisa , Wigzell Hans 
Published: December 2022

AbstractInfection with Chlamydia pneumoniae is a common cause of acute respiratory disease in man and is also associated with atherosclerotic cardiovascular disorder. Herein, we have compared bacterial load and immune parameters of C. pneumoniae-infected mice genomically lacking T cell coreceptors, cytokine receptors, or cytotoxic effector molecules. A protective role for CD8+ cells is shown by the enhanced severity of infection of CD8−/− or TAP-1−/−/β2-microglobulin −/− mice. CD8+ cells hindered a parasite growth-promoting role of CD4+ T cells, as indicated by the higher sensitivity to early infection of CD8−/− than CD4−/−/CD8−/− mice, which was further confirmed in experiments in which SCID mice were reconstituted with either CD4+ or CD4+ plus CD8+ T cells. Interestingly, CD4+ T cells played a dual role, detrimental early (14 and 24 days) after infection but protective at later time points (60 days after infection). The CD8+ T cell protection was perforin independent. The early deleterious role of CD4+ in the absence of CD8+ T cells was associated with enhanced IL-4 and IL-10 mRNA levels and delayed IFN-γ mRNA accumulation in lungs. In line with this, IFN-γR−/− (but not TNFRp55 −/−) mice showed dramatically increased susceptibility to C. pneumoniae, linked to reduced inducible nitric oxide synthase (iNOS) mRNA accumulation, but not to diminished levels of specific Abs. The increased susceptibility of iNOS−/− mice indicates a protective role for iNOS activity during infection with C. pneumoniae. The higher sensitivity of IFN-γR−/− mice to C. pneumoniae compared with that of SCID or recombination-activating gene-1−/− mice suggested a relevant protective role of IFN-γ-dependent innate mechanisms of protection.
Qualitative and Quantitative Requirements for CD4+ T Cell-Mediated Antiviral Protection
Authors: Maloy Kevin J. , Burkhart Christoph , Freer Giulia , Rülicke Thomas , Pircher Hanspeter , Kono Dwight H. , Theofilopoulos Argyrios N. , Ludewig Burkhard , Hoffmann-Rohrer Urs , Zinkernagel Rolf M. , Hengartner Hans 
Published: December 2022

AbstractCD4+ Th cells deliver the cognate and cytokine signals that promote the production of protective virus-neutralizing IgG by specific B cells and are also able to mediate direct antiviral effector functions. To quantitatively and qualitatively analyze the antiviral functions of CD4+ Th cells, we generated transgenic mice (tg7) expressing an MHC class II (I-Ab)-restricted TCR specific for a peptide derived from the glycoprotein (G) of vesicular stomatitis virus (VSV). The elevated precursor frequency of naive VSV-specific Th cells in tg7 mice led to a markedly accelerated and enhanced class switching to virus-neutralizing IgG after immunization with inactivated VSV. Furthermore, in contrast to nontransgenic controls, tg7 mice rapidly cleared a recombinant vaccinia virus expressing the VSV-G (Vacc-IND-G) from peripheral organs. By adoptive transfer of naive tg7 CD4+ T cells into T cell-deficient recipients, we found that 105 transferred CD4+ T cells were sufficient to induce isotype switching after challenge with a suboptimal dose of inactivated VSV. In contrast, naive transgenic CD4+ T cells were unable to adoptively confer protection against peripheral infection with Vacc-IND-G. However, tg7 CD4+ T cells that had been primed in vitro with VSV-G peptide were able to adoptively transfer protection against Vacc-IND-G. These results demonstrate that the antiviral properties of CD4+ T cells are governed by the differentiation status of the CD4+ T cell and by the type of effector response required for virus elimination.
Experimental Murine Schistosomiasis in the Absence of B7 Costimulatory Molecules: Reversal of Elicited T Cell Cytokine Profile and Partial Inhibition of Egg Granuloma Formation
Authors: Hernandez Hector J. , Sharpe Arlene H. , Stadecker Miguel J. 
Published: December 2022

AbstractThe granulomatous inflammation in infection with the helminth Schistosoma mansoni represents a cellular hypersensitivity reaction mediated by, and dependent upon, MHC class II-restricted CD4+ Th cells sensitized to parasite egg Ags. The current work examines the role and significance of the B7:CD28/CTLA-4 pathway in providing the costimulation necessary for the activation of these pathogenic T cells. In vitro T cell responses in B7-1−/− mice, 7–8 wk postinfection, were no different from wild-type controls, but the absence of B7-2 molecules resulted in a decrease in egg Ag-induced proliferation with increased IFN-γ production. Both B7-1−/− and B7-2−/− mice exhibited intact granuloma formation. In contrast, CD4+ Th cells from B7-1/2 double-deficient mice displayed a dramatic loss of proliferative capacity upon stimulation with egg Ag. Most strikingly, these T cells secreted only IFN-γ, but not IL-4 and IL-10, a pattern entirely opposite to that displayed by wild-type controls. Despite these major differences in T cell reactivity, B7-1/2−/− mice had only a limited reduction of granuloma size and fibrosis, without appreciable difference in cellular composition. These results show that substantial granuloma formation can occur under conditions of limited T cell expansion and restricted Th1-type cytokine production. They also support the notion that the combined effect of B7 signaling is not as critical for Th1 cell activation as it is for the development of the Th2 dominant environment characteristic of the evolving schistosome infection in H-2b mice.
Bacterial Lipopolysaccharide Causes Rapid Shedding, Followed by Inhibition of mRNA Expression, of the IL-1 Type II Receptor, with Concomitant Up-Regulation of the Type I Receptor and Induction of Incompletely Spliced Transcripts
Authors: Penton-Rol Giselle , Orlando Simone , Polentarutti Nadia , Bernasconi Sergio , Muzio Marta , Introna Martino , Mantovani Alberto 
Published: December 2022

AbstractThe IL-1 type I receptor (IL-1RI) is part of a signaling complex together with the IL-1R accessory protein, whereas available information is consistent with a “decoy” model of function for the IL-1 type II receptor (IL-1RII). The present study was designed to investigate the effect of bacterial LPS on IL-1R in human monocytes. LPS causes rapid release of the IL-1RII, an effect blocked by a metalloprotease inhibitor. Subsequently, LPS-treated monocytes showed a drastic reduction of IL-1RII mRNA. In contrast, LPS induced IL-1RI and, to a lesser extent, IL-1AcP expression. LPS-induced augmented expression of the canonical 5-kb IL-1RI mRNA was accompanied by the appearance of 2.4-kb IL-1RI transcripts. The use of probes representative of different regions of the IL-1RI mRNA, as well as cDNA cloning, revealed that the 2.4-kb inducible band includes incompletely spliced, polyadenylated transcripts potentially encoding truncated versions of the receptor. The observation that the prototypic proinflammatory molecule LPS has divergent effects on IL-1Rs, with inhibition of IL-1RII and stimulation of IL-1RI and IL-1R accessory protein, is consistent with the view that these molecules subserve opposite functions in the pathophysiology of the IL-1 system. The rapid shedding of IL-1RII by monocytes early in recruitment may serve to buffer the systemic action of IL-1 leaking from sites of inflammation. This early event, followed by prolonged inhibition of IL-1RII expression and up-regulation of IL-1RI, may render monocytes more responsive to IL-1 at sites of inflammation.
Differential Regulation of Eosinophil Chemokine Signaling Via CCR3 and Non-CCR3 Pathways
Authors: Sabroe Ian , Hartnell Adele , Jopling Louise A. , Bel Sandra , Ponath Paul D. , Pease James E. , Collins Paul D. , Williams Timothy J. 
Published: December 2022

AbstractTo investigate eosinophil stimulation by chemokines we developed a sensitive assay of leukocyte shape change, the gated autofluorescence/forward scatter assay. Leukocyte shape change responses are mediated through rearrangements of the cellular cytoskeleton in a dynamic process typically resulting in a polarized cell and are essential to the processes of leukocyte migration from the microcirculation into sites of inflammation. We examined the actions of the chemokines eotaxin, eotaxin-2, monocyte chemoattractant protein-1 (MCP-1), MCP-3, MCP-4, RANTES, macrophage inflammatory protein-1α (MIP-1α), and IL-8 on leukocytes in mixed cell suspensions and focused on the responses of eosinophils to C-C chemokines. Those chemokines acting on CCR3 induced a rapid shape change in eosinophils from all donors; of these, eotaxin and eotaxin-2 were the most potent. Responses to MCP-4 were qualitatively different, showing marked reversal of shape change responses with agonist concentration and duration of treatment. In contrast, MIP-1α induced a potent response in eosinophils from a small and previously undescribed subgroup of donors via a non-CCR3 pathway likely to be CCR1 mediated. Incubation of leukocytes at 37°C for 90 min in the absence of extracellular calcium up-regulated responses to MCP-4 and MIP-1α in the majority of donors, and there was a small increase in responses to eotaxin. MIP-1α responsiveness in vivo may therefore be a function of both CCR1 expression levels and the regulated efficiency of coupling to intracellular signaling pathways. The observed up-regulation of MIP-1α signaling via non-CCR3 pathways may play a role in eosinophil recruitment in inflammatory states such as occurs in the asthmatic lung.
Corticotropin-Releasing Factor Receptor 1 in Mouse Spleen: Expression After Immune Stimulation and Identification of Receptor-Bearing Cells
Authors: Radulovic Marko , Dautzenberg Frank M. , Sydow Sabine , Radulovic Jelena , Spiess Joachim 
Published: December 2022

AbstractA specific polyclonal Ab against the N-terminal domain of corticotropin-releasing factor (CRF) receptor, type 1 (CRF-R1), was employed to an immunohistochemical analysis of the spleen from naive mice and mice exposed to an immune challenge. Cell types stained with anti-CRF-R1 Ab were identified by their nuclear shapes and colocalization with the cell type-specific markers ER-MP58, ER-MP20, Moma-1, Moma 2, anti-CD3e mAbs, and anti-Ig Ab. Only a few clusters of CRF-R1+ cells were found in spleen sections of naive mice at sites typical for granulopoietic islands. However, a 17-fold increase in the mean number of CRF-R1+ cells was noted within hours following a challenge of acute systemic inflammation induced by i.p. administration of LPS. The majority of these cells were identified as mature neutrophils. CRF-R1 was shown to mediate suppression of the IL-1β secretion by these cells. However, at later time points a large number of granulocyte-macrophage precursors was strongly labeled with anti-CRF-R1 Ab. Western blot analysis of splenic membranes from animals treated with LPS revealed a m.w. of approximately 70,000 for CRF-R1. Subcellular staining patterns were suggestive for the predominant localization of CRF-R1 on granule membranes. CRF-R1 mRNA was detected in spleen but not in bone marrow and peripheral blood leukocytes from naive mice. Thus, it was indicated that CRF-R1 was not produced constitutively by mature or immature neutrophils. Its production was rather triggered by inflammatory stimuli.
Macrophage Inflammatory Protein-2 Is Required for Neutrophil Passage Across the Epithelial Barrier of the Infected Urinary Tract
Authors: Hang Long , Haraoka Masashi , Agace William W. , Leffler Hakon , Burdick Marie , Strieter Robert , Svanborg Catharina 
Published: December 2022

Abstract
IL-8 is a major human neutrophil chemoattractant at mucosal infection sites. This study examined the C-X-C chemokine response to mucosal infection, and, specifically, the role of macrophage inflammatory protein (MIP)-2, one of the mouse IL-8 equivalents, for neutrophil-epithelial interactions. Following intravesical Escherichia coli infection, several C-X-C chemokines were secreted into the urine, but only MIP-2 concentrations correlated to neutrophil numbers. Tissue quantitation demonstrated that kidney MIP-2 production was triggered by infection, and immunohistochemistry identified the kidney epithelium as a main source of MIP-2. Treatment with anti-MIP-2 Ab reduced the urine neutrophil numbers, but the mice had normal tissue neutrophil levels. By immunohistochemistry, the neutrophils were found in aggregates under the pelvic epithelium, but in control mice the neutrophils crossed the urothelium into the urine. The results demonstrate that different chemokines direct neutrophil migration from the bloodstream to the lamina propria and across the epithelium and that MIP-2 serves the latter function. These findings suggest that neutrophils cross epithelial cell barriers in a highly regulated manner in response to chemokines elaborated at this site. This is yet another mechanism that defines the mucosal compartment and differentiates the local from the systemic host response.
Induction of Autoimmunity by Multivalent Immunodominant and Subdominant T Cell Determinants of La (SS-B)
Authors: Farris A. Darise , Brown Lorena , Reynolds Pakathip , Harley John B. , James Judith A. , Scofield R. Hal , McCluskey James , Gordon Tom P. 
Published: December 2022

AbstractWe investigated the consequences of altering the form and valence of defined autodeterminants on the initiation and spreading of experimentally induced La/Ro autoimmunity. Anti-La and Ro (SS-A) Ab responses were monitored following immunization of healthy mice with defined immunodominant and subdominant T cell determinants of the La (SS-B) autoantigen synthesized as either monomeric or multiple antigenic (MAP) peptides. Abs to mouse La (mLa) developed faster and were of higher titer in mice immunized with the subdominant mLa25–44 MAP compared with mice immunized with the 25–44 monomer. Rapid intermolecular spreading of the autoimmune response to 60-kDa Ro was observed in AKR/J mice immunized with mLa25–44 MAP, but not in mice immunized repeatedly with monomeric peptide. A/J mice immunized and boosted with the known tolerogenic mLa287–301 determinant delivered as monomeric peptide failed to develop Abs to either intact mLa or mLa287–301 peptide. However, immunization with the multivalent mLa287–301 peptide led to the rapid production of high titer mLa autoantibodies associated with a proliferative T cell response to the mLa287–301 peptide. The data suggested that the enhanced immunogenicity of MAPs was not due to augmented Ag presentation or T cell stimulation. However, MAP-, but not monomer peptide-, containing immune complexes were potent substrates for Ab-dependent fixation of complement. These results demonstrate that the form of Ag responsible for inducing autoimmunity can profoundly influence the nature and magnitude of the immune response. Thus, molecular mimicry of tolerogenic and nontolerogenic self determinants might trigger autoimmunity under conditions of altered valence.
Cutting Edge: 4-1BB Is a Bona Fide CD8 T Cell Survival Signal
Authors: Takahashi Chikara , Mittler Robert S. , Vella Anthony T. 
Published: December 2022

AbstractAfter recognition of Ag/MHC and ligation of a costimulatory molecule, resting T cells will clonally expand and then delete to very low levels. Previously, it was shown that deletion can be prevented by coinjection of cytokines or proinflammatory agents such as adjuvants. Here, we demonstrate that ligation of 4-1BB blocks deletion of superantigen-activated T cells in the absence of adjuvant or additional cytokine treatment. Nearly 10 times as many staphylococcal enterotoxin A-specific T cells were detected in the spleens of mice injected 21 days previously with staphylococcal enterotoxin A and an agonist anti-4-1BB Ab compared with mice given staphylococcal enterotoxin A and a control IgG. Even though both CD4- and CD8-activated T cells expressed 4-1BB, a higher proportion of CD8 T cells were rescued compared CD4 T cells. These data suggest that although 4-1BB provides costimulation, it may also promote long-term T cell survival.
Cutting Edge: An Inducible Sialidase Regulates the Hyaluronic Acid Binding Ability of CD44-Bearing Human Monocytes
Authors: Katoh Shigeki , Miyagi Taeko , Taniguchi Haruko , Matsubara Yu-ichi , Kadota Jun-ichi , Tominaga Akira , Kincade Paul W. , Matsukura Shigeru , Kohno Shigeru 
Published: December 2022

AbstractPrevious studies established that variable degrees and types of glycosylation can account for differences in the ability of CD44 to function as a receptor for hyaluronic acid. We have now used neuraminidase treatment to conclude that sialylation negatively regulates CD44 on the human monocytic cell line THP-1 and peripheral blood monocytes. Both of these cell types displayed increased receptor activity after overnight culture with LPS. Of particular interest, the sialidase inhibitor 2-deoxy-2,3-dehydro-N-acetylneuraminic acid completely blocked the LPS induced recognition of hyaluronic acid by THP-1 cells. Furthermore, acquisition of this characteristic paralleled induction of one type of sialidase activity. Monocytes may be capable of enzymaticly remodeling cell surface CD44, altering their ability to interact with the extracellular matrix.
An Essential Role for NF-κB in IL-18-Induced IFN-γ Expression in KG-1 Cells
Authors: Kojima Hirotada , Aizawa Yasushi , Yanai Yoshiaki , Nagaoka Katsue , Takeuchi Makoto , Ohta Tsunetaka , Ikegami Hakuo , Ikeda Masao , Kurimoto Masashi 
Published: December 2022

AbstractIL-18 is a multifunctional cytokine playing various regulatory roles in the immune system including induced cytokine production. As a part of our ongoing studies on the molecular mechanisms of IL-18-induced IFN-γ production, we have examined the transcriptional regulation of the IFN-γ gene by IL-18 in a human myelomonocytic cell line, KG-1. On the basis of DNA/protein binding, we have determined an IL-18-inducible NF-κB binding site located at −786 to −776 of the IFN-γ gene regulatory region (designated KBBsite). Transient transfection of promoter-reporter gene constructs revealed that the KBBsite is required for full IL-18-induced activation of the IFN-γ gene transcription induced by IL-18. In addition, stable transformants of a dominant-negative form of the IκBα showed an inhibition of IL-18-dependent IκBα degradation, NF-κB activation, and expression of IFN-γ. These results are the first to show the actual significance of the NF-κB pathway in the regulation of IFN-γ gene expression by IL-18.
Thymic Shared Antigen-2: A Novel Cell Surface Marker Associated with T Cell Differentiation and Activation
Authors: Berzins Stuart P. , Davey Gayle M. , Randle-Barrett Elise S. , Malin Mark A. , Classon Brendan J. , Fraser Stuart , Boyd Richard L. 
Published: December 2022

AbstractThymic shared Ag-2 (TSA-2) is a 28-kDa, glycophosphatidylinitosol-linked cell surface molecule expressed on various T cell and thymic stromal cell subsets. It is expressed on most CD3−CD4−CD8−, CD4+CD8+, and CD3highCD4−CD8+ thymocytes but is down-regulated on ∼40% of CD3highCD4+CD8− thymocytes. Expression on peripheral TCR-αβ+ T cells is similar to that of CD3+ thymocytes, although a transient down-regulation occurs with cell activation. Consistent with the recent hypothesis that emigration from the thymus is an active process, recent thymic emigrants are primarily TSA-2−/low. TSA-2 expression reveals heterogeneity among subpopulations of CD3highCD4+CD8− thymocytes and TCR-γδ+ T cell previously regarded as homogenous. The functional importance of TSA-2 was illustrated by the severe block in T cell differentiation caused by adding purified anti-TSA-2 mAb to reconstituted fetal thymic organ culture. While each CD25/CD44-defined triple-negative subset was present, differentiation beyond the TN stage was essentially absent, and cell numbers of all subsets were significantly below those of control cultures. Cross-linking TSA-2 on thymocytes caused a significant Ca2+ influx but no increase in apoptosis, unless anti-TSA-2 was used in conjunction with suboptimal anti-CD3 mAb. Similar treatment of mature TSA-2+ T cells had no effect on cell survival or proliferation. This study reveals TSA-2 to be a functionally important molecule in T cell development and a novel indicator of heterogeneity among a variety of developing and mature T cell populations.