bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Acute Lung Inflammatory Injury by Endogenous IL-13
Authors: Lentsch Alex B. , Czermak Boris J. , Jordan Jacqueline A. , Ward Peter A. 
Published: December 2022

AbstractUsing IgG immune complex deposition to trigger acute lung inflammation in rats, we have previously shown that exogenously administered IL-13 suppresses the acute inflammatory response. In the same model, expression of both mRNA and protein for IL-13 has now been detected. Treatment of rats with Ab to IL-13 accentuated the inflammatory response, with significant increases in lung vascular permeability and in the number of neutrophils in bronchoalveolar lavage fluids. In the presence of anti-IL-13, activation of the transcription factor, NF-κB, was significantly increased in lung. In addition, anti-IL-13 caused significant increases in bronchoalveolar lavage levels of TNF-α, macrophage inflammatory protein-2, and cytokine-inducible neutrophil chemoattractant but no changes in lung vascular ICAM-1. These data suggest that during lung inflammation endogenous IL-13 regulates NF-κB activation and related cytokine/chemokine generation, all of which determines the intensity of the lung inflammatory response.
IL-18 Is Produced by Articular Chondrocytes and Induces Proinflammatory and Catabolic Responses
Authors: Olee Tsaiwei , Hashimoto Sanshiro , Quach Jacqueline , Lotz Martin 
Published: December 2022

AbstractIL-18, a cytokine originally identified as IFN-γ-inducing factor, is a member of the IL-1 family of proteins. Because IL-1α and IL-1β are important mediators in the pathogenesis of arthritis, the present study addresses the expression of IL-18 and its role in regulating in articular chondrocytes. IL-18 mRNA was induced by IL-1β in chondrocytes. Chondrocytes produced the IL-18 precursor and in response to IL-1 stimulation secreted the mature form of IL-18. Studies on IL-18 effects on chondrocytes showed that it inhibits TGF-β-induced proliferation and enhances nitric oxide production. IL-18 stimulated the expression of several genes in normal human articular chondrocytes including inducible nitric oxide synthase, inducible cyclooxygenase, IL-6, and stromelysin. Gene expression was associated with the synthesis of the corresponding proteins. Treatment of normal human articular cartilage with IL-18 increased the release of glycosaminoglycans. These finding identify IL-18 as a cytokine that regulates chondrocyte responses and contributes to cartilage degradation.
Immunogenicity and Protective Efficacy of Tuberculosis DNA Vaccines Encoding Putative Phosphate Transport Receptors
Authors: Tanghe Audrey , Lefèvre Philippe , Denis Olivier , D’Souza Sushila , Braibant Martine , Lozes Evelyne , Singh Mahavir , Montgomery Donna , Content Jean , Huygen Kris 
Published: December 2022

AbstractUsing culture filtrate Ag-specific mAbs generated from mycobacteria-infected H-2b haplotype mice, we have previously identified three genes in the Mycobacterium tuberculosis genome, encoding proteins homologous to the periplasmic ATP-binding cassette phosphate-binding receptor PstS of the phosphate-specific transport system of E. coli. To define the potential vaccinal properties of these phosphate-binding proteins, female C57BL/6 mice were injected i.m. with plasmid DNA encoding PstS-1, PstS-2, or PstS-3 proteins from M. tuberculosis and immunogenicity and protective efficacy against i.v. challenge with M. tuberculosis H37Rv was analyzed. Significant levels of highly Ag-specific Abs and Th1-type cytokines IL-2 and IFN-γ could be detected following vaccination with each of the three genes. However, only mice vaccinated with PstS-3 DNA demonstrated significant and sustained reduction in bacterial CFU numbers in spleen and lungs for 3 mo after M. tuberculosis challenge, as compared with CFU counts in mice vaccinated with control DNA. Vaccination with PstS-2 DNA induced a modest reduction in CFU counts in spleen only, whereas vaccination with PstS-1 DNA was completely ineffective in reducing bacterial multiplication. In conclusion, our results indicate that DNA vaccination is a powerful and easy method for comparative screening of potentially protective Ags from M. tuberculosis and that the PstS-3 protein is a promising new subunit vaccine candidate.
Cutting Edge: Protective Effects of Notch-1 on TCR-Induced Apoptosis
Authors: Jehn Birgit M. , Bielke Wolfgang , Pear Warren S. , Osborne Barbara A. 
Published: December 2022

Abstract
The Notch receptor protein was originally identified in Drosophila and is known to mediate cell to cell communication and influence cell fate decisions. Members of this family have been isolated from invertebrates as well as vertebrates. We isolated mouse Notch-1 in a yeast two-hybrid screen with Nur77, which is a protein that has been shown previously to be required for apoptosis in T cell lines. The data presented below indicate that Notch-1 expression provides significant protection to T cell lines from TCR-mediated apoptosis. These data demonstrate a new antiapoptotic role for Notch-1, providing evidence that, in addition to regulating cell fate decisions, Notch-1 can play a critical role in controlling levels of cell death in T cells.
Differential Requirement of IFN Consensus Sequence Binding Protein for the Production of IL-12 and Induction of Th1-Type Cells in Response to IFN-γ
Authors: Wu Chang-You , Maeda Haruko , Contursi Cristina , Ozato Keiko , Seder Robert A. 
Published: December 2022

AbstractIFN-γ exerts multiple biological activities in the modulation of immune responses by the induction of transcription factors. One transcriptional factor of the IFN regulatory factor family found to be critical in regulating IL-12-dependent IFN-γ production in vivo following infectious challenge has been designated IFN consensus sequence-binding protein (ICSBP). In this study, the role of ICSBP in regulating type 1 responses to T cell-specific stimulation in vitro was assessed. Total splenocytes from ICSBP−/− mice stimulated with soluble anti-CD3 were markedly impaired in the production of IFN-γ compared with similarly stimulated cells from ICSBP+/+ mice. Consistent with the decrease in IFN-γ production, splenocytes from ICSBP−/− mice stimulated with anti-CD3 in the presence or absence of IFN-γ or a soluble CD40 ligand agonist failed to produce IL-12 p40 and IL-12 p70 protein; however, the deficient production of IFN-γ from ICSBP−/− mice could be restored by the addition of anti-CD28 Ab in an IL-12-independent manner. In contrast to the previous data, production of IFN-γ from naive CD4+/LECAM-1high cells of ICSBP−/− mice that had been primed in vitro with anti-CD3 was similar to or greater than that of ICSBP+/+ controls. In addition, the presence of IFN-γ in priming cultures enhanced both priming for IFN-γ and IL-12 responsiveness from ICSBP−/− CD4+ T cells. Overall, these results provide evidence that ICSBP is differentially required for the ability of IFN-γ to regulate type 1 cytokine responses from APCs and CD4+ T cells.
Persistence of Autoreactive T Cell Drive Is Required to Elicit Anti-Chromatin Antibodies in a Murine Model of Drug-Induced Lupus
Authors: Kretz-Rommel Anke , Rubin Robert L. 
Published: December 2022

AbstractLong-term treatment with procainamide and numerous other medications is occasionally associated with the development of drug-induced lupus. We recently established a murine model for this syndrome by disrupting central T cell tolerance. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, into (C57BL/6 × DBA/2)F1 mice resulted in the appearance of chromatin-reactive T cells and anti-chromatin autoantibodies. The current study explores in this model the role of autoreactive T cells in autoantibody production and examines why autoantibodies after a single intrathymic drug injection were much more limited in isotype and specificity. Injection of as few as 5000 chromatin-reactive T cells into naive, syngeneic mice induced a rapid IgM anti-denatured DNA response, while injection of at least 100-fold greater number of activated T cells was required for induction of IgG anti-chromatin Abs, suggesting that small numbers of autoreactive T cells can be homeostatically controlled. Mice subjected to a single intrathymic PAHA injection after receiving splenic B cells from an intrathymic PAHA-injected syngeneic donor also developed anti-chromatin Abs, but adoptive transfer of similarly primed T cells or of B cells without intrathymic PAHA injection of the recipient failed to produce an anti-chromatin response. However, anti-chromatin Abs developed after a single intrathymic PAHA injection in Fas-deficient C57BL/6-lpr/lpr mice, suggesting that activation-induced cell death limited autoimmunity in normal mice. Taken together, these results imply that chromatin-reactive T cells produced by intrathymic PAHA created a B cell population primed to somatically mutate and Ig class switch when subjected to a heavy load or second wave of autoreactive T cells.
Cutting Edge: Coordinate Regulation of IFN Regulatory Factor-1 and the Polymeric Ig Receptor by Proinflammatory Cytokines
Authors: Blanch Vincent J. , Piskurich Janet F. , Kaetzel Charlotte S. 
Published: December 2022

AbstractThe polymeric IgR (pIgR) mediates transcytosis of IgA across epithelial barriers of mucous membranes and exocrine glands. Synthesis of pIgR is up-regulated by the proinflammatory cytokines TNF-α, IFN-γ, and IL-1 in HT-29 human colon carcinoma cells. We previously reported that IFN-γ and TNF-α induce production of the transcription factor IFN regulatory factor-1 (IRF-1) in HT-29 cells and that IRF-1 binds to an element in exon 1 of the PIGR gene. We now report that levels of IRF-1 and pIgR mRNA are coordinately regulated in HT-29 cells by TNF-α, IFN-γ, and IL-1β. Furthermore, we demonstrate that in vivo expression of pIgR mRNA is greatly depressed in the intestine and liver of IRF-1-deficient mice. Our findings indicate a major role for the IRF-1 transcription factor in regulation of the PIGR gene and suggest a model for regulation of important genes in the mucosal immune system by proinflammatory cytokines.
CD4-Mediated Inhibiton of IL-2 Production in Activated T Cells
Authors: Bonnard Madeleine , Haughn Loralee , Julius Michael 
Published: December 2022

AbstractThe role of CD4 in T cell activation has been attributed to its capacity to increase the avidity of interaction with APC and to shuttle associated Lck to the TCR/CD3 activation complex. The results presented in this study demonstrate that ligation of CD4 inhibits ongoing responses of preactivated T cells. Specifically, delayed addition of CD4-specific mAb is shown to inhibit Ag- or mAb-induced responses of both primary T cells and T cell clonal variants. The Ag responses of the latter are independent of the adhesion provided by CD4; thus the observed inhibition is not due to blocking CD4-MHC interactions. Further, analysis of the clonal variants demonstrates that CD4-associated Lck is not essential for the inhibition observed, as anti-CD4 inhibits responses of clonal variants, expressing a form of CD4 unable to associate with Lck (double cysteine-mutated CD4). The inhibition is counteracted by the addition of exogenous IL-2, demonstrating that the block is not due to a lesion in IL-2 utilization, rather its production. It is demonstrated that the delayed addition of anti-CD4 results in a rapid reduction in steady-state levels of IL-2 mRNA in both primary T cells and clonal variants.
Isolation of MHC Class I-Restricted Tumor Antigen Peptide and Its Precursors Associated with Heat Shock Proteins hsp70, hsp90, and gp96
Authors: Ishii Tatsuaki , Udono Heiichiro , Yamano Taketoshi , Ohta Hiroyuki , Uenaka Akiko , Ono Toshiro , Hizuta Akio , Tanaka Noriaki , Srivastava Pramod K. , Nakayama Eiichi 
Published: December 2022

Abstract
We have previously demonstrated that vaccination with heat shock proteins hsp70, hsp90, and gp96 elicits specific immunity against the tumor from which the hsps were purified. Although the association of tumor Ag peptides with these hsps have been suggested, the identification of the peptides or their precursors stripped from the hsps remained to be resolved. We show in this report that an Ld-restricted cytotoxic T lymphocyte epitope of a mouse leukemia RL♂1 and its precursors are associated with the chaperones hsp90 and hsp70 in the cytosol and gp96 in the lumen of the endoplasmic reticulum. Hsp70 was associated with only final sized octamer, while hsp90 was found to associate with the octamer and two distinct precursor peptides. The gp96 was associated with the octamer and one of the two precursors. Thus, each of the hsps bound a distinct set of peptides. Our results have demonstrated for the first time that the hsps associate not only with final sized tumor Ag peptide but also with its precursors. The implication of this evidence is also discussed in terms of the roles of hsps in MHC class I Ag processing/presentation.
Lipopolysaccharide Inhibits TNF-Induced Apoptosis: Role of Nuclear Factor-κB Activation and Reactive Oxygen Intermediates
Authors: Manna Sunil K. , Aggarwal Bharat B. 
Published: December 2022

AbstractLPS, a component of the cell wall in Gram-negative bacteria, induces inflammation and septic shock syndrome by stimulating various inflammatory cytokines including TNF. How LPS affects the TNF-mediated cellular responses, however, is not understood. In this study, the effect of LPS on TNF-mediated apoptosis in human histiocytic lymphoma U-937 cells was investigated. We found that treatment of cells with LPS completely abolished TNF-mediated cytotoxicity and activation of caspase-3. LPS-chelating antibiotic, polymyxin B, suppressed the antiapoptotic activity, indicating the specificity of the effect. Within minutes, LPS through CD14 induced the activation of NF-κB, degradation of IκBα (inhibitory subunit of NF-κB) and IκBβ, and nuclear translocation of p65. An antioxidant, pyrrolidine dithiocarbamate, which blocked LPS-induced NF-κB activation, also abolished the antiapoptotic effects of LPS at the same time. Besides TNF, the apoptosis induced by taxol and okadaic acid was also sensitive to LPS-induced NF-κB activation, whereas that induced by H2O2, doxorubicin, daunomycin, vincristine, and vinblastine was NF-κB insensitive. Tumor cells that constitutively expressed NF-κB also showed resistance to the apoptotic effects of TNF, taxol, and okadaic acid, but sensitivity to all other agents, indicating the critical role of NF-κB in blocking apoptosis induced by certain agents. Overall, these results indicate that LPS induces resistance to the apoptotic effects of TNF and other agents, and that NF-κB activation, whether induced or constitutive, inhibits this apoptosis.
Specific Activated T Cells Regulate IL-12 Production by Human Monocytes Stimulated with Cryptococcus neoformans
Authors: Retini Cinzia , Casadevall Arturo , Pietrella Donatella , Monari Claudia , Palazzetti Barbara , Vecchiarelli Anna 
Published: December 2022

Abstract
IL-12 production mediated by a T cell-independent and/or T cell-dependent pathway was investigated in human monocytes responding to Cryptococcus neoformans. The data of this study showed that: 1) appreciable levels of IL-12 were observed when freshly isolated monocytes were exposed to acapsular C. neoformans or Candida albicans and secretion occurred within 24–48 h of incubation; 2) monocytes alone were poor producers of IL-12 when stimulated with encapsulated C. neoformans; 3) the presence of specific anti-glucuronoxylomannan mAb favored IL-12 secretion and Fc cross-linking could play a role; 4) monocytes were able to secrete consistent levels of IL-12 when cultured with activated T cells responding to C. neoformans; 5) the maximum secretion of IL-12 was observed at 5–7 days of culture and was strongly regulated by the presence of endogenous IFN-γ; and 6) the interaction between CD40 on monocytes and CD40 ligand on activated T lymphocytes responding to C. neoformans played a critical role in IL-12 secretion. These data highlight the mechanisms of IL-12 production by human monocytes exposed to C. neoformans, indicating a possible biphasic secretion of IL-12, dependent on the direct effect of fungal insult, and characterized by consistent secretion of IL-12 that is dependent on the interaction of CD40 with the CD40 ligand expressed on activated T cells responding to C. neoformans.
Role of TNF-α in Pulmonary Host Defense in Murine Invasive Aspergillosis
Authors: Mehrad Borna , Strieter Robert M. , Standiford Theodore J. 
Published: December 2022

AbstractInvasive pulmonary aspergillosis is a common and devastating complication of immunosuppression, whose incidence has increased dramatically in tandem with the increase in the number of immunocompromised patients. Given the role of TNF-α in other pulmonary infections, we hypothesized that TNF-α is an important proximal signal in murine invasive pulmonary aspergillosis. Intratracheal challenge with Aspergillus fumigatus conidia in both neutropenic (cyclophosphamide-treated) and nonneutropenic BALB/c mice resulted in the time-dependent increase in lung TNF-α levels, which correlated with the histologic development of a patchy, peribronchial infiltration of mononuclear and polymorphonuclear cells. Ab-mediated neutralization of TNF-α resulted in an increase in mortality in both normal and cyclophosphamide-treated animals, which was associated with increased lung fungal burden as determined by histology and as quantified by chitin content. Depletion of TNF-α resulted in a reduced lung neutrophil influx in both normal and cyclophosphamide-treated animals, which occurred in association with a decrease in lung levels of the C-X-C chemokine, macrophage inflammatory protein-2 and the C-C chemokines macrophage inflammatory protein-1α and JE. In cyclophosphamide-treated animals, intratracheal administration of a TNF-α agonist peptide (TNF70–80) 3 days before, but not concomitant with, the administration of Aspergillus conidia resulted in improved survival from 9% in control mice to 55% in TNF70–80-treated animals. These studies indicate that TNF-α is a critical component of innate immunity in both immunocompromised and immunocompetent hosts, and that pretreatment with a TNF-α agonist peptide in a compartmentalized fashion can significantly enhance resistance to A. fumigatus in neutropenic animals.
IFN-γ Is Required for Viral Clearance from Central Nervous System Oligodendroglia
Authors: Parra Beatriz , Hinton David R. , Marten Norman W. , Bergmann Cornelia C. , Lin Mark T. , Yang Camillia S. , Stohlman Stephen A. 
Published: December 2022

Abstract
Infection of the central nervous system (CNS) by the JHM strain of mouse hepatitis virus (JHMV) is a rodent model of the human demyelinating disease multiple sclerosis. The inability of effective host immune responses to eliminate virus from the CNS results in a chronic infection associated with ongoing recurrent demyelination. JHMV infects a variety of CNS cell types during the acute phase of infection including ependymal cells, astrocytes, microglia, oligodendroglia, and rarely in neurons. Replication within the majority of CNS cell types is controlled by perforin-dependent virus-specific CTL. However, inhibition of viral replication in oligodendroglia occurs via a perforin-independent mechanism(s). The potential role for IFN-γ as mediator controlling JHMV replication in oligodendroglia was examined in mice deficient in IFN-γ secretion (IFN-γ0/0 mice). IFN-γ0/0 mice exhibited increased clinical symptoms and mortality associated with persistent virus, demonstrating an inability to control replication. Neither antiviral Ab nor CTL responses were diminished in the absence of IFN-γ, although increased IgG1 was detected in IFN-γ0/0 mice. Increased virus Ag in the absence of IFN-γ localized almost exclusively to oligodendroglia and was associated with increased CD8+ T cells localized within white matter. These data suggest that although perforin-dependent CTL control virus replication within astrocytes and microglia, which constitute the majority of infected CNS cells, IFN-γ is critical for control of viral replication in oligodendroglia. Therefore, different mechanisms are used by the host defenses to control virus replication within the CNS, dependent upon the phenotype of the targets of virus replication.
VCAM-1 Expression on Human Dermal Microvascular Endothelial Cells Is Directly and Specifically Up-Regulated by Substance P
Authors: Quinlan Kimberly L. , Song In-Sung , Naik Shubhada M. , Letran Eleanor L. , Olerud John E. , Bunnett Nigel W. , Armstrong Cheryl A. , Caughman S. Wright , Ansel John C. 
Published: December 2022

AbstractSensory nerves in skin are capable of releasing multiple neuropeptides, which modulate inflammatory responses by activating specific cutaneous target cells. Extravasation of particular subsets of leukocytes depends upon the regulated expression of cellular adhesion molecules such as VCAM-1 on microvascular endothelial cells. We examined the direct effect of cutaneous neuropeptides on the expression and function of human dermal microvascular endothelial cell (HDMEC) VCAM-1. A significant increase in VCAM-1 immunostaining of microvascular endothelium was observed in vivo following capsaicin application to human skin. Multiple cutaneous sensory C-fiber-released neuropeptides were evaluated for their ability to induce VCAM-1 cell surface expression on HDMEC. Only substance P (SP) was found to be capable of inducing HDMEC VCAM-1 expression. This SP-mediated VCAM-1 induction appeared to be a direct effect that did not require the release of other HDMEC-derived soluble factors. Increased HDMEC VCAM-1 mRNA expression was detected 1 h after the addition of SP, with peak mRNA increase at 6–9 h postinduction. FACS studies demonstrated a 6.5-fold increase in endothelial cell surface VCAM-1 expression detectable 16 h after addition of SP, which was specifically blocked by a neurokinin-1 receptor antagonist. Increased VCAM-1 cell surface expression on SP-treated HDMEC resulted in a 4-fold increase in the functional binding of 51Cr-labeled MOLT-4 T cells. These data indicate that SP is capable of directly and specifically up-regulating functional endothelial VCAM-1 expression and thus may play a key role in modulating certain inflammatory responses in the skin.