bluuebunny/crossref_metadata_2025_split huggingface dataset:
NF-κB-Inducing Kinase Is a Common Mediator of IL-17-, TNF-α-, and IL-1β-Induced Chemokine Promoter Activation in Intestinal Epithelial Cells
Authors: Awane Masaaki , Andres Pietro G. , Li Dan Jun , Reinecker Hans-Christian 
Published: December 2022

AbstractIL-17 expression is restricted to activated T cells, whereas the IL-17R is expressed in a variety of cell types including intestinal epithelial cells. However, the functional responses of intestinal epithelial cells to stimulation with IL-17 are unknown. Moreover, the signal transduction pathways activated by the IL-17R have not been characterized. IL-17 induced NF-κB protein-DNA complexes consisting of p65/p50 heterodimers in the rat intestinal epithelial cell line IEC-6. The induction of NF-κB correlated with the induction of CXC and CC chemokine mRNA expression in IEC-6 cells. IL-17 acted in a synergistic fashion with IL-1β to induce the NF-κB site-dependent CINC promoter. Induction of the CINC promoter by IL-17 in IEC-6 cells was TNF receptor-associated factor-6 (TRAF6), but not TRAF2, dependent. Furthermore, IL-17 induction of the CINC promoter could be inhibited by kinase-negative mutants of NF-κB-inducing kinase and IκB kinase-α. In addition to activation of the NF-κB, IL-17 regulated the activities of extracellular regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases in IEC-6 cells. Whereas the IL-17-mediated activation of extracellular regulated kinase mitogen-activated protein kinases was mediated through ras, c-Jun N-terminal kinase activation was dependent on functional TRAF6. These data suggest that NF-κB-inducing kinase serves as the common mediator in the NF-κB signaling cascades triggered by IL-17, TNF-α, and IL-1β in intestinal epithelial cells.
HLA Class I-Mediated Induction of Cell Proliferation Involves Cyclin E-Mediated Inactivation of Rb Function and Induction of E2F Activity
Authors: Nath Niharika , Bian Hong , Reed Elaine F. , Chellappan Srikumar P. 
Published: December 2022

AbstractChronic rejection of transplanted organs is manifested as atherosclerosis of the blood vessels of the allograft. HLA class I Ags have been implicated to play a major role in this process, since signaling via HLA class I molecules can induce the proliferation of aortic endothelial as well as smooth muscle cells. In this study, we show that HLA class I-mediated induction of cell proliferation correlates with inactivation of the Rb protein in the T cell line Jurkat as well as human aortic endothelial cells. HLA class I-mediated inactivation of Rb can be inhibited specifically by neutralizing Abs to basic fibroblast growth factor (bFGF), suggesting a role for FGF receptors in the signaling process. Signaling through HLA class I molecules induced cyclin E-associated kinase activity within 4 h in quiescent endothelial cells, and appeared to mediate the inactivation of Rb. A cdk2 inhibitor, Olomoucine, as well as a dominant-negative cdk2 construct prevented HLA class I-mediated inactivation of Rb; in contrast, dominant-negative cdk4 and cdk6 constructs had no effect. Furthermore, there was no increase in cyclin D-associated kinase activity upon HLA class I ligation, suggesting that cyclin E-dependent kinase activity mediates Rb inactivation, leading to E2F activation and cell proliferation.
The Role of p38 Mitogen-Activated Protein Kinase in IL-1β Transcription
Authors: Baldassare Joseph J. , Bi Yanhua , Bellone Clifford J. 
Published: December 2022

AbstractSeveral reports have shown that bicyclic imidazoles, specific inhibitors of the p38 mitogen-activated protein kinase (MAPK), block cytokine synthesis at the translational level. In this study, we examined the role of p38 MAPK in the regulation of the IL-1β cytokine gene in monocytic cell lines using the bicyclic imidazole SB203580. Addition of SB203580 30 min before stimulation of monocytes with LPS inhibited IL-1β protein and steady state message in a dose-dependent manner in both RAW264.7 and J774 cell lines. The loss of IL-1β message was due mainly to inhibition of transcription, since nuclear run-off analysis showed an ∼80% decrease in specific IL-1 RNA synthesis. In contrast, SB203580 had no effect on the synthesis of TNF-α message. LPS-stimulated p38 MAPK activity in the RAW264.7 cells was blocked by SB203580, as measured by the inhibition of MAPKAP2 kinase activity, a downstream target of the p38 MAPK. CCAATT/enhancer binding protein (C/EBP)/NFIL-6-driven chloramphenicol acetyltransferase (CAT) reporter activity was sensitive to SB203580, indicating that C/EBP/NFIL-6 transcription factor(s) are also targets of p38 MAPK. In contrast, transfected CAT constructs containing NF-κB elements were only partially inhibited (∼35%) at the highest concentration of SB203580 after LPS stimulation. As measured by EMSA, LPS-stimulated NF-κB activation was not affected by SB203580. Overall, the results demonstrate, for the first time, a role for p38 MAPK in IL-1β transcription by acting through C/EBP/NFIL-6 transcription factors.
Peptide Recognition by Two HLA-A2/Tax11–19-Specific T Cell Clones in Relationship to Their MHC/Peptide/TCR Crystal Structures
Authors: Hausmann Stefan , Biddison William E. , Smith Kathrine J. , Ding Yuan-Hua , Garboczi David N. , Utz Ursula , Wiley Don C. , Wucherpfennig Kai W. 
Published: December 2022

Abstract
The crystal structures of two human TCRs specific for a HTLV-I Tax peptide bound to HLA-A2 were recently determined, for the first time allowing a functional comparison of TCRs for which the MHC/peptide/TCR structures are known. Extensive amino acid substitutions show that the native Tax residues are optimal at each peptide position. A prominent feature of the TCR contact surface is a deep pocket that accommodates a tyrosine at position 5 of the peptide. For one of these TCRs, this pocket is highly specific for aromatic residues. In the other TCR structure, this pocket is larger, allowing many different residues to be accommodated. The CTL clones also show major differences in the specificity for several other peptide residues, including side chains that are not directly contacted by the TCR. Despite the specificity of these clones, peptides that are distinct at five or six positions from Tax11–19 induce CTL activity, indicating that substantial changes of the peptide surface are tolerated. Human peptides with limited sequence homology to Tax11–19 represent partial TCR agonists for these CTL clones. The distinct functional properties of these CTL clones highlight structural features that determine TCR specificity and cross-reactivity for MHC-bound peptides.
T Cell Responses to Gram-Negative Intracellular Bacterial Pathogens: A Role for CD8+ T Cells in Immunity toSalmonellaInfection and the Involvement of MHC Class Ib Molecules
Authors: Lo Wei-Feng , Ong Helena , Metcalf Eleanor S. , Soloski Mark J. 
Published: December 2022

AbstractDespite being a major group of intracellular pathogens, the role of class I-restricted T cells in the clearance of Gram-negative bacteria is not resolved. Using a murine typhoid model, a role for class I-restricted T cells in the immune response to the Gram-negative pathogen Salmonella typhimurium is revealed. Class I-deficient β2-microglobulin−/− mice show increased susceptibility to infection with S. typhimurium. Following infection, CD8+ CTLs specific for Salmonella-infected targets can be readily detected. The Salmonella-specific CTLs recognize infected H-2-mismatched targets, suggesting the involvement of shared class Ib molecules. Studies using transfectants expressing defined class Ia and class Ib molecules indicate the involvement of the class Ib molecule, Qa-1. Ab-blocking studies and the measurement of bacteria-specific CTL frequencies identified Qa-1 as a dominant restricting element. The Qa-1-restricted CTL recognition depends on TAP and proteasome functions. Surprisingly, Qa-1-restricted CTLs recognized cells infected with other closely related Gram-negative bacteria. Taken together, these observations indicate that Salmonella-specific CTLs recognize a cross-reactive epitope presented by Qa-1 molecules and, as such, may be novel targets for vaccine development.
CD8+ T Cells Are a Biologically Relevant Source of Macrophage Inflammatory Protein-1α In Vivo
Authors: Cook Donald N. , Smithies Oliver , Strieter Robert M. , Frelinger Jeffrey A. , Serody Jonathan S. 
Published: December 2022

AbstractChemokines are small proteins that direct the migration of leukocytes to inflammatory foci. Many cell types, including macrophages, fibroblasts, endothelial cells, and lymphocytes, produce chemokines in vitro, but biologically relevant sources of chemokines in vivo have not been well characterized. To investigate the pertinent sources of macrophage inflammatory protein-1α (MIP-1α) in vivo, we used MIP-1α-deficient (MIP-1α−/−) mice as donors and as recipients in adoptive transfer experiments after a lethal infection with Listeria monocytogenes (LM). Unexpectedly, we found that the production of MIP-1α by CD8+ T cells was critical in this system, as the cells from MIP-1α−/− mice primed with LM were significantly less effective in protecting naive mice against a lethal infection by LM than were the CD8+ T cells from wild-type (wt) mice. This requirement for donor T cell production of MIP-1α was confirmed by the observation that wt donor T cells do not mediate protection when coadministered with an anti-MIP-1α polyclonal antiserum. Production of MIP-1α by the recipient mice was not required for protection, because wt and MIP-1α−/− recipients were equally well protected by wt T cells. A 2- to 3-fold decrease in the number of transferred lymphocytes was seen in the spleens of mice receiving T cells from MIP-1α−/− mice compared with those receiving wt T cells. In addition, CD8+ T cells from MIP-1α−/− mice had a reduced ability to kill LM-infected target cells in vitro. These findings demonstrate that T cell production of MIP-1α is required for clearance of an intracellular pathogen in vivo.
Inhibition of a Membrane Complement Regulatory Protein by a Monoclonal Antibody Induces Acute Lethal Shock in Rats Primed with Lipopolysaccharide
Authors: Mizuno Masashi , Nishikawa Kazuhiro , Okada Noriko , Matsuo Seiichi , Ito Kenichi , Okada Hidechika 
Published: December 2022

AbstractRats pretreated with traces of LPS developed acute fatal shock syndrome after i.v. administration of a mAb that inhibits the function of a membrane complement regulatory molecule. Such a shock was not observed after the administration of large amounts of LPS instead of the mAb following LPS pretreatment. The lethal response did not occur in rats depleted of either leukocytes or complement, and a C5a receptor antagonist was found to inhibit the reaction. Furthermore, LPS-treated rats did not suffer fatal shock following the injection of cobra venom factor, which activates complement in the fluid phase so extensively as to exhaust complement capacity. Therefore, complement activation on cell membranes is a requirement for this type of acute reaction.
Ischemia/Reperfusion-Induced IFN-γ Up-Regulation: Involvement of IL-12 and IL-18
Authors: Daemen Marc A. R. C. , Veer Cornelis van′t , Wolfs Tim G. A. M. , Buurman Wim A. 
Published: December 2022

AbstractTissue injury as a consequence of ischemia followed by reperfusion is characterized by early as well as late signs of inflammation. The latter, among others, involves IFN-γ-dependent up-regulation of MHC class I and II Ag expression. Employing a murine model of renal ischemia, we show that renal IL-18 mRNA up-regulation coincides with caspase-1 activation at day 1 following ischemia. IFN-γ and IL-12 mRNA are subsequently up-regulated at day 6 following ischemia. Combined, but not separate, in vivo neutralization of the IFN-γ inducing cytokines IL-12 and IL-18 reduces IFN-γ-dependent MHC class I and II up-regulation to a similar extent as IFN-γ neutralization, suggesting the involvement of functional IL-12, IL-18, and IFN-γ protein. These results reveal a novel relationship between tissue injury of nonmicrobial origin and the induction of IL-12 as well as IL-18. The collaboration observed between endogenous IL-12 and IL-18 in the induction of IFN-γ after renal ischemia/reperfusion, resembles the immune response to bacterial infections.
Mast Cell Expression of Gelatinases A and B Is Regulated bykitLigand and TGF-β
Authors: Fang Kenneth C. , Wolters Paul J. , Steinhoff Martin , Bidgol Afshin , Blount John L. , Caughey George H. 
Published: December 2022

AbstractOur prior work shows that cultured BR cells derived from dog mastocytomas secrete the 92-kDa proenzyme form of gelatinase B. We provided a possible link between mast cell activation and metalloproteinase-mediated matrix degradation by demonstrating that α-chymase, a serine protease released from secretory granules by degranulating mast cells, converts progelatinase B to an enzymatically active form. The current work shows that these cells also secrete gelatinase A. Furthermore, gelatinases A and B both colocalize to α-chymase-expressing cells of canine airway, suggesting that normal mast cells are a source of gelatinases in the lung. In BR cells, gelatinase B and α-chymase expression are regulated, whereas gelatinase A expression is constitutive. Progelatinase B mRNA and enzyme expression are strongly induced by the critical mast cell growth factor, kit ligand, which is produced by fibroblasts and other stromal cells. Induction of progelatinase B is blocked by U-73122, Ro31-8220, and thapsigargin, implicating phospholipase C, protein kinase C, and Ca2+, respectively, in the kit ligand effect. The profibrotic cytokine TGF-β virtually abolishes the gelatinase B mRNA signal and also attenuates kit ligand-mediated induction of gelatinase B expression, suggesting that an excess of TGF-β in inflamed or injured tissues may alter mast cell expression of gelatinase B, which is implicated in extracellular matrix degradation, angiogenesis, and apoptosis. In summary, these data provide the first evidence that normal mast cells express gelatinases A and B and suggest pathways by which their regulated expression by mast cells can influence matrix remodeling and fibrosis.
Decreased IL-12 Production Underlies the Decreased Ability of Male Lymph Node Cells to Induce Experimental Autoimmune Encephalomyelitis
Authors: Kim Sookhyun , Voskuhl Rhonda R. 
Published: December 2022

AbstractMyelin basic protein (MBP)-specific T lymphocytes from male SJL mice were shown to be less encephalitogenic than MBP-specific T lymphocytes from females. Mechanisms underlying this gender difference in the induction phase of EAE were examined. Following immunization with MBP, draining lymph nodes contained fewer cells, and Ag-specific proliferative responses were decreased in males as compared with females. These gender differences in the proliferative response were not unique to MBP-specific responses since they were also observed after immunization with hen eggwhite lysozyme. Short-term MBP-specific T cell lines derived from females and males mapped with identical specificity, indicating no defect in the ability of male APCs to process Ag. Interestingly, IL-12 and IFN-γ production was decreased following Ag-specific stimulation of draining lymph node cells (LNC) from males as compared with females, but IL-10 and IL-4 were no different. While male-derived LNCs were less encephalitogenic than female derived LNCs, cotransfer and coculture of male LNCs with female LNCs demonstrated that male LNCs were not immunosuppressive. Administration of IL-12 to LNCs from male mice enhanced encephalitogenicity. These data indicate that deficient endogenous IL-12 production within draining LNCs of male SJL mice is central to gender differences in the induction phase of experimental autoimmune encephalomyelitis.
Emergence of Regulatory CD4+ T Cell Response to Repetitive Stimulation with Antigen-Presenting Cells In Vitro: Implications in Designing Antigen-Presenting Cell-Based Tumor Vaccines
Authors: Chakraborty Nitya G. , Li Li , Sporn Jonathan R. , Kurtzman Scott H. , Ergin M. T. , Mukherji Bijay 
Published: December 2022

AbstractBecause APCs play a crucial role in the generation of T cell-mediated immune responses, numerous clinical trials with APC-based vaccines have been initiated in different types of human cancers. Encouraging results have emerged from some of these initial studies. Thus far, APC-based vaccinations usually include multiple rounds of immunization. With this approach, although we and others have detected induction of Ag-specific CTL responses in vaccinated patients after stimulation with the same APC-based immunogen, in vitro we also find that repetitive in vitro stimulation with Ag-loaded APC can, at times, lead to the emergence of noncytolytic CD4+ T cells exhibiting the characteristic phenotype of Th2 cells. These noncytolytic CD4+ T cells synthesize large quantities of type 2 cytokines such as IL-4 and IL-10 on stimulation with the autologous APC or tumor cells in an MHC class II-restricted manner. Further, these CD4+ T cells and a cell-free supernatant factor block the activation of fresh T lymphocytes. The supernatant factor also exhibits a marked inhibitory effect on the expression of the costimulatory molecules, CD80 and CD86, by APC. The inhibitory effect of the supernatant factor can be abrogated by neutralizing IL-10 in the supernatant. These observations therefore have implications in the APC-based tumor vaccine protocol design.
An Adoptive Transfer Model of Allergic Lung Inflammation in Mice Is Mediated by CD4+CD62LlowCD25+ T Cells
Authors: Wise James T. , Baginski Theodore J. , Mobley James L. 
Published: December 2022

AbstractAnimal models of allergic lung inflammation have provided important insight into the cellular and biochemical factors involved in the pathogenesis of human asthma. Herein, we describe an adoptive transfer model of OVA-specific eosinophilic lung inflammation in the mouse that is used to characterize the cells involved in mediating the pulmonary inflammatory response. We report that freshly isolated spleen cells from OVA-sensitized mice are unable to prime naive recipient mice to respond to a subsequent OVA aerosol challenge. Subjecting the spleen cells to short term restimulation with Ag in vitro, however, renders the cells competent to transfer activity. The magnitude and the kinetics of the eosinophilic pulmonary inflammation in the adoptive transfer recipients are nearly identical with those generated by a more conventional active sensitization/challenge protocol, with the notable exception of differential production of plasma IgE in the two models. Extensive negative and positive selection of splenocyte subtypes indicates that the transfer of Ag-primed CD4+ T cells is both necessary and sufficient to establish full responsiveness in the recipient mice. Additional phenotypic characterization of the transfer-reactive CD4+ T cells indicates that they are found within the CD62LlowCD25+ subset and secrete high levels of IL-5 in response to Ag stimulation. Limiting dilution analysis-derived minimal frequency estimates indicate that approximately 1 in 8500 of the sensitized, cultured spleen cells produces IL-5 in response to OVA stimulation in vitro, suggesting that eosinophilic lung inflammation can be induced in naive mice by the transfer of &lt;1200 Ag-specific CD4+ T cells.
Down-Regulation of Human Basophil IgE and FCεRIα Surface Densities and Mediator Release by Anti-IgE-Infusions Is Reversible In Vitro and In Vivo
Authors: Saini Sarbjit S. , MacGlashan Donald W. , Sterbinsky Sherry A. , Togias Alkis , Adelman Daniel C. , Lichtenstein Lawrence M. , Bochner Bruce S. 
Published: December 2022

AbstractPreviously, infusions of an anti-IgE mAb (rhumAb-E25) in subjects decreased serum IgE levels, basophil IgE and FcεRIα surface density, and polyclonal anti-IgE and Ag-induced basophil histamine release responses. We hypothesized that these effects would be reversed in vivo by discontinuation of infusions and in vitro by exposing basophils to IgE. Subjects received rhumAb-E25 biweekly for 46 wk. Blood samples taken 0–52 wk after rhumAb-E25 were analyzed for serum IgE and basophil expression of IgE, FcεRIα, and CD32. Basophil numbers were unaffected by infusions. Eight weeks after infusions, free IgE levels rose in vivo but did not reach baseline. Basophil IgE and FcεRIα rose in parallel with free IgE while CD32 was stable. FcεRI densities, measured by acid elution, returned to 80% of baseline, whereas histamine release responses returned to baseline. Basophils cultured with or without IgE or IgG were analyzed for expression of IgE, FcεRIα, and CD32. By 7 days with IgE, expression of IgE and FcεRIα rose significantly, whereas cultures without IgE declined. IgE culture did not effect CD32. IgG culture did not effect expression of any marker. The present results strongly suggest that free IgE levels regulate FcεRIα expression on basophils.
Differential Modulation of Human Epidermal Langerhans Cell Maturation by Ultraviolet B Radiation
Authors: Nakagawa Satoshi , Koomen Cock W. , Bos Jan D. , Teunissen Marcel B. M. 
Published: December 2022

AbstractUVB irradiation of the skin causes immunosuppression and Ag-specific tolerance in which Langerhans cells (LC) are involved. We tested the effect of UVB on LC that had migrated out of cultured epidermal sheets derived from the skin that was irradiated ex vivo (200, 400, 800, or 1600 J/m2). Two separate subpopulations of LC were distinguished: large-sized LC with high HLA-DR expression, and HLA-DR-low, small LC. UVB stimulated the maturation of the former LC subset as demonstrated by enhanced up-regulation of CD80, CD86, CD54, CD40, and CD83 and reduced CD1a expression in comparison with unirradiated controls. In contrast, the latter LC exhibited little or no up-regulation of these molecules except for high CD1a expression and high binding of annexin V, indicating that they were apoptotic, although their CD95 expression was relatively low. Stimulation of enriched LC with CD40 ligand-transfected cells and IFN-γ revealed that the release of IL-1β, IL-6, IL-8, and TNF-α was enhanced by UVB. In comparison with HLA-DR-low LC, HLA-DR-high LC were the principal IL-8 producers as demonstrated by intracellular cytokine staining, and they retained more accessory function. There was no detectable secretion of IL-12 p70, and IL-18 production was neither affected by any stimulus nor by UVB. These results suggest a dual action of UVB on LC when irradiated in situ: 1) immunosuppression by preventing maturation and inducing apoptotic cell death in part of LC, and 2) immunopotentiation by enhancing the up-regulation of costimulatory molecules and the production of proinflammatory cytokines in another part.