bluuebunny/crossref_metadata_2025_split huggingface dataset:
The IL-1 Receptor-Related T1 Antigen Is Expressed on Immature and Mature Mast Cells and on Fetal Blood Mast Cell Progenitors
Authors: Moritz Dirk R. , Rodewald Hans-Reimer , Gheyselinck Jacqueline , Klemenz Roman 
Published: December 2022

Abstract
Expression of the T1 gene, also known as ST2, DER4, and Fit-1, has been shown to be associated with cell proliferation. It gives rise to two different mRNAs that encode a receptor-like protein and a soluble molecule representing the ectodomain of the receptor form. Although T1 is a member of the IL-1R family, its biologic function is currently unknown. In this study, we have analyzed the expression of the T1 surface Ag in murine hemopoietic organs. Mast cells (MCs) were shown to be the only identifiable cell lineage that expressed T1 at high levels. T1 expression was found on cultured bone marrow-derived immature MCs. Similarly, freshly isolated connective tissue-type MCs from the i.p. cavity were also shown to express high levels of T1. Interestingly, the earliest detectable committed MC precursor isolated from fetal blood (FB) at day 15.5 of gestation, but not circulating hemopoietic stem cells in FB, also expresses high level of T1. Since FB promastocytes lack expression of the high affinity IgE receptor (FcεRI), T1 expression precedes expression of FcεRI in MC ontogeny. The finding that the T1 Ag is selectively expressed at several stages during development of the MC lineage suggests that this cell surface molecule, in combination with the well-established markers c-Kit and FcεRI, should be valuable for studying the MC lineage.
A His19 to Ala Mutant of Melanoma Growth-Stimulating Activity Is a Partial Antagonist of the CXCR2 Receptor
Authors: Baly Deborah L. , Horuk Richard , Yansura Daniel G. , Simmons Laura C. , Fairbrother Wayne J. , Kotts Claire , Wirth Cindy M. , Gillece-Castro Beth L. , Toy Karen , Hesselgesser Joseph , Allison David E. 
Published: December 2022

Abstract
Melanoma growth stimulating activity (MGSA) and IL-8 are related chemokines that are potent chemoattractants and activators of neutrophils both in vitro and in vivo. Increasing evidence suggests that these molecules play an important role in inflammation; thus, antagonists of their action could be useful therapeutically as antiinflammatory agents. We have generated an MGSA mutant, H19A, that shows a dissociation between receptor binding and biologic activity. The biologic activity of the H19A mutant is between 133-fold and 282-fold less potent than that of wild-type MGSA measured by three independent assays of neutrophil function, i.e., elastase release chemotaxis and the up-regulation of CD18. In addition, pretreatment of cells with the H19A mutant inhibited the ability of MGSA to induce elastase release and chemotaxis and to increase intracellular calcium. However, competition binding studies in cells transfected with the CXCR2 receptor and in neutrophils demonstrate that the receptor affinity of the H19A mutant is only 13-fold less than that of wild-type MGSA. These studies suggest that the mutant MGSA is defective in activating signaling through the receptor and indicate that binding to the receptor is not sufficient to activate a biologic response. The dissociation between receptor binding and activation for this mutant suggests that it should be possible to design antagonists of MGSA that may be of clinical utility.
Activation of the RON Receptor Tyrosine Kinase Inhibits Inducible Nitric Oxide Synthase (iNOS) Expression by Murine Peritoneal Exudate Macrophages: Phosphatidylinositol-3 Kinase Is Required for RON-Mediated Inhibition of iNOS Expression
Authors: Chen Yi-Qing , Fisher James H. , Wang Ming-Hai 
Published: December 2022

AbstractRON (recepteur d’origine nantais) is a receptor tyrosine kinase expressed in murine peritoneal resident macrophages and activated by macrophage-stimulating protein (MSP). The objectives of this investigation were to study the RON expression in exudate macrophages and the mechanisms by which RON inhibits inducible nitric oxide synthase (iNOS) expression induced by LPS and IFN-γ. We found that mouse peritoneal resident and Con A-elicited macrophages collected on day 3 or day 5 express RON. Acute exudate macrophages collected on day 1 did not express RON. Activation of RON inhibited LPS- and IFN-γ-induced macrophage nitric oxide production and iNOS mRNA accumulation. Similar inhibition was observed also in Raw264.7 macrophage cell lines transfected with human RON cDNA. In these cells, MSP induced RON phosphorylation concomitant with reduced iNOS mRNA expression and protein synthesis. Further, we show that activated RON inhibited the iNOS gene transcription activity as assessed by chloramphenicol acetyltransferase activity in Raw264.7 cells expressing RON. Wortmannin, a specific inhibitor of phosphatidylinositol-3 (PI-3) kinase, prevented the inhibitory effect of RON on the iNOS gene promoter activity and on the nitric oxide production induced by LPS and IFN-γ. These effects were confirmed further by introducing a dominant-inhibitory PI-3 kinase p85 subunit in RON-expressing Rwa264.7 cells. Taken together, our results suggest that RON is expressed in peritoneal macrophages at later stages of inflammation. Activation of RON by MSP in mature exudate macrophages inhibits LPS- and IFN-γ-induced iNOS synthesis. PI-3 kinase is an important effector molecule required for RON-mediated inhibition of iNOS expression in macrophages.
HLA-DQ6/8 Double Transgenic Mice Develop Auricular Chondritis Following Type II Collagen Immunization: A Model for Human Relapsing Polychondritis
Authors: Bradley David S. , Das Pritam , Griffiths Marie M. , Luthra Harvinder S. , David Chella S. 
Published: December 2022

Abstract
We have generated transgenic (tg) mice expressing HLA-DQ8αβ (DQA1*0301/DQB*0302) or HLA-DQ6αβ (DQA1*0103/DQB1*0601) molecules lacking endogenous murine class II expression (Aβ0) to investigate the ability of these HLA class II to present type II collagen (CII) and induce collagen-induced arthritis. The DQ8αβ tg mice responded strongly to CII, developing severe arthritis, while DQ6αβ tg mice were nonresponsive to CII. The addition of the mixed haplotype DQ8α6β molecule did not significantly influence CII reactivity. To examine the interaction of DQ6αβ and DQ8αβ molecules in vivo, we generated double tg DQ6αβ/8αβ (Aβ0) mice expressing both the α- and β-chains of DQ6 and DQ8 molecules by mating DQ6αβ (Aβ0) and DQ8αβ (Aβ0) tg mice. CII-immunized DQ6αβ/8αβ tg mice developed severe experimental polychondritis, exhibiting both polyarthritis and auricular chondritis. The clinical, serologic, and histologic manifestations of experimental polychondritis are similar to those symptoms in human relapsing polychondritis. The susceptibility of DQ6αβ/8αβ tg mice compared with resistance in the parental strains suggests that expression of both the DQ6αβ and DQ8αβ tgs, unique to the DQ6αβ8αβ tg strain, is important in susceptibility to experimental polychondritis. The DQ6αβ/8αβ tg mice provide a model to investigate putative autoantigens and the mechanisms of pathogenesis involved in relapsing polychondritis as well as the influence of the expression of multiple HLA class II molecules on the disease process.
Cutting Edge: Immunoregulation of Th Cells by Naturally Processed Peptide Antagonists
Authors: Carson Richard T. , Desai Dharmesh D. , Vignali Kate M. , Vignali2 Dario A. A. 
Published: December 2022

AbstractTh cells recognize protein Ags as short peptides bound to MHC class II molecules. Altered peptide ligands can antagonize (inhibit) T cell responses to stimulatory peptides. Peptides generated by APC may contain peptide flanking residues (PFR), which lie outside the minimal binding epitope and can be recognized by the TCR. Our data show that PFR-dependent T cells were found to be potently antagonized by peptides that lack PFR and responded poorly to native protein or the immunogenic epitope delivered by a recombinant influenza virus. These data provide the first evidence that Ag processing generates both stimulatory and antagonist peptides from a single immunogenic epitope, an observation that may have important implications for T cell immunoregulation and autoimmunity.
Use of Intranasal IL-12 to Target Predominantly Th1 Responses to Nasal and Th2 Responses to Oral Vaccines Given with Cholera Toxin
Authors: Marinaro Mariarosaria , Boyaka Prosper N. , Jackson Raymond J. , Finkelman Fred D. , Kiyono Hiroshi , Jirillo Emilio , McGhee Jerry R. 
Published: December 2022

AbstractWe have investigated the effects of IL-12 and cholera toxin (CT) on the immune response to tetanus toxoid (TT) given by intranasal or oral routes. CT inhibited IL-12-induced IFN-γ secretion both in vivo and in vitro. Intranasal administration of IL-12 to mice nasally immunized with the combined vaccine of TT and CT resulted in increased TT-specific IgG2a and IgG3 Abs, while IgG1 and IgE Ab responses were markedly reduced. This shift of the CT-induced immune response toward Th1 type was associated with TT-specific CD4+ T cells secreting IFN-γ and reduced levels of Th2-type cytokines (i.e., IL-4, IL-5, IL-6, and IL-10). In contrast, intranasal IL-12 enhanced the CT-induced serum IgG1 and IgE Ab responses in mice given the combined vaccine orally. IFN-γ secretion by TT-specific CD4+ T cells was also enhanced; however, Th2-type cytokine responses were predominant. Mucosal secretory IgA responses to oral or nasal vaccines were not affected by intranasal IL-12. Thus, intranasal IL-12 delivery influences Th cell subset development in mucosal inductive sites that are dependent on the route of vaccine delivery.
Structural Features of Autoreactive TCR That Determine the Degree of Degeneracy in Peptide Recognition
Authors: Hausmann Stefan , Martin Margarita , Gauthier Laurent , Wucherpfennig Kai W. 
Published: December 2022

AbstractStructural aspects of human TCRs that allow the activation of autoreactive T cells by diverse microbial peptides were examined using two human myelin basic protein (MBP)-specific T cell clones. The TCR sequences of these clones differed only in the N region of TCR-α and -β since the clones had the same Vα-Jα and Vβ-Jβ rearrangements. The two clones had a similar fine specificity for the MBP peptide, except for the P5 position of the peptide (lysine). In the crystal structure of the HLA-DR2/MBP peptide complex, P5 lysine is a prominent, solvent-exposed residue in the center of the DR2/MBP peptide surface. Five microbial peptides with conservative or nonconservative changes at the P5 position (lysine to arginine, serine, or proline) activated one of these clones. In contrast, the other clone was activated only by three of these peptides which had a conservative lysine to arginine change at P5. The degree of specificity/degeneracy in recognition of the P5 side chain was the key difference between these TCRs since the Escherichia coli/Haemophilus influenzae peptide stimulated both clones when the P5 position was substituted from serine to arginine. These results demonstrate that the complementarity-determining region 3 loops contribute to the degree of degeneracy in peptide recognition by human MBP-specific TCRs.
Characterization of the Signal Transduction Pathway Activated in Human Monocytes and Dendritic Cells by MPIF-1, a Specific Ligand for CC Chemokine Receptor 1
Authors: Nardelli Bernardetta , Tiffany H. Lee , Bong Gary W. , Yourey Pamela A. , Morahan Diana K. , Li Yuling , Murphy Philip M. , Alderson Ralph F. 
Published: December 2022

AbstractThe receptor specificity and signal transduction pathway has been identified and characterized for a truncated form of myeloid progenitor inhibitory factor-1 (MPIF-124–99). MPIF-1 binds specifically to sites, in particular CCR1, shared with macrophage inflammatory protein-1α (MIP-1α) on the surface of human monocytes and dendritic cells, as inferred by its ability to compete for [125I]MIP-1α, but not for [125I]MIP-1β or [125I]monocyte chemotactic protein-1(MCP-1) binding to intact cells. Based on calcium flux, MPIF-1 is an agonist on CCR1-transfected HEK-293 cells, monocytes, and dendritic cells, but not on CCR5-, CCR8-, or CX3CR1-transfected cells. The inhibitory effect of guanosine 5′-O-(3-thio-triphosphate) (GTP-γS) or pertussis toxin pretreatment on MPIF-1 binding and calcium mobilization, respectively, indicates the involvement of G proteins in the interaction of MPIF-1 and its receptor(s). The increase in intracellular free calcium concentration following MPIF-1 treatment is mainly due to the influx of calcium from an extracellular pool. However, a portion of the intracellular free calcium concentration is derived from a phospholipase C inhibitor-sensitive intracellular pool. MPIF-1 induces a rapid dose-dependent release of [3H]arachidonic acid from monocytes that is dependent on extracellular calcium and is blocked by phospholipase A2 (PLA2) inhibitors. Furthermore, PLA2 activation is shown to be necessary for filamentous actin formation in monocytes. Thus, the MPIF-1 signal transduction pathway appears to include binding to CCR1; transduction by G proteins; effector function by phospholipase C, protein kinase C, calcium flux, and PLA2; and cytoskeletal remodeling.
Inhibition of Allergic Airway Inflammation in Mice Lacking Nitric Oxide Synthase 2
Authors: Xiong Yelin , Karupiah Gunasegaran , Hogan Simon P. , Foster Paul S. , Ramsay Alistair J. 
Published: December 2022

AbstractWe have used mice rendered deficient for nitric oxide synthase 2 (NOS2) production to study the role of inducible nitric oxide (NO) in the pathogenesis of allergic airways disease. Using a model with OVA as aeroallergen, we show that the manifestations of disease, including infiltration of inflammatory cells, particularly eosinophils, loss of structural integrity of the airway walls, microvascular leakage, pulmonary edema, and airway occlusion are markedly less severe in the NOS2 mutants than in wild-type animals. Indeed, NOS2-deficiency resulted in a 55–60% reduction in both circulatory and pulmonary eosinophil numbers following aeroallergen treatment, although eosinophil maturation or efflux from the bone marrow was not suppressed. There were no obvious differences in levels of airway hyperreactivity recorded in OVA-treated wild-type and NOS2-deficient mice. Interestingly, the suppression of allergic inflammation was accompanied by marked increases in T cell production of IFN-γ but not by any obvious reduction in the secretion of either IL-4 or IL-5, nor by major changes in the IgG1 and IgE OVA-specific serum Ig profiles in the mutants. The markedly enhanced production of IFN-γ in NOS2−/− mice was apparently responsible for the suppression of both eosinophilia and disease, as in vivo depletion of this factor restored allergic pathology in these animals. Our data indicate that NOS2 promotes allergic inflammation in airways via down-regulation of IFN-γ activity and suggest that inhibitors of this molecule may represent a worthwhile therapeutic strategy for allergic diseases including asthma.
Regulation of IL-6 Synthesis in Human Peripheral Blood Mononuclear Cells by C3a and C3adesArg
Authors: Fischer Wolfgang H. , Jagels Mark A. , Hugli Tony E. 
Published: December 2022

AbstractThe anaphylatoxin C3a has been reported to have immunomodulatory effects on a number of different cell types. In this study we investigated the effects of C3a and C3adesArg on gene expression and protein secretion of IL-6 in human PBMCs, either alone or in combination with LPS or IL-1β. C3a or C3adesArg alone exhibited no effect on the expression or secretion of IL-6. However, when PBMC were stimulated with LPS or IL-1β, both C3a and C3adesArg were found to enhance IL-6 release by PBMC in a dose-dependent manner. Since C3a has been shown to induce PGE2 production by monocytes, and PGE2 has been shown to influence cytokine production, we investigated the potential role of PGE2 in C3a-mediated enhancement of LPS- and IL-1β-induced IL-6 production. Indomethacin blocked PGE2 release, but had no influence on the observed effects of C3a, suggesting that the effects of C3a on IL-6 production are independent of PGE2 formation by monocytes. Northern blot analysis showed that C3a as well as C3adesArg enhanced LPS-induced mRNA levels for IL-6. Pretreatment of PBMCs with pertussis toxin blocked the functions of C3a and C3adesArg, indicating that the actions of these two molecules are mediated by a G protein-coupled pathway. Furthermore, we investigated the effects of C3a and C3adesArg on induction of NF-κB and activating protein-1 binding. Both molecules enhanced LPS-induced NF-κB and activating protein-1 binding activity. These results demonstrate the capacity of intact C3a and its circulating des-Arg form to exert immunmodulatory effects in vitro.
Effect of Taxol and Taxotere on Gene Expression in Macrophages: Induction of the Prostaglandin H Synthase-2 Isoenzyme
Authors: Moos Philip J. , Muskardin D. T. , Fitzpatrick F. A. 
Published: December 2022

AbstractInduction of genes encoding cytokines or other, unidentified proteins may contribute to the pharmacological effects of taxol. We hypothesized that prostaglandin H synthase-2 (PGHS-2) was one of the unidentified genes induced by taxol. Taxol alone or taxol plus IFN-γ increased PGE2 formation, PGHS-2 protein expression, and PGHS-2 mRNA expression in RAW 264.7 murine macrophages. The kinetics for mRNA induction, protein expression, and catalysis were self-consistent. A selective inhibitor of PGHS-2 blocked PGE2 formation by cells incubated with taxol; a selective inhibitor of PGHS-1 had no effect. A glucocorticoid blocked the induction of mRNA, the expression of PGHS-2 protein, and the formation of PGE2. Neither taxol alone nor taxol plus IFN-γ altered the expression of the PGHS-1 isoenzyme in RAW 264.7 cells. Taxotere, an analogue that stabilizes microtubules as potently as taxol, did not alter the expression of PGHS-2, implying that its induction in RAW 264.7 murine macrophages did not originate from microtubule stabilization. Taxol and taxotere each induced PGHS-2 expression in human monocytes suspended in 10% human serum. However, human monocytes suspended in 10% bovine serum responded only to LPS, not to taxol or taxotere, implying that they act independently of the LPS-mimetic process that is prominent in mice. Taxol induced PGHS-2 in human and murine monocytes via a p38 mitogen-associated protein kinase pathway. The inclusion of PGHS-2 among the early response genes induced in leukocytes may be relevant to the beneficial and adverse effects encountered during taxol administration.
IL-13 Production by NK Cells: IL-13-Producing NK and T Cells Are Present In Vivo in the Absence of IFN-γ
Authors: Hoshino Tomoaki , Winkler-Pickett Robin T. , Mason Anna T. , Ortaldo John R. , Young Howard A. 
Published: December 2022

AbstractIn this study, we demonstrate that human NK cells, human NK clones, the human NK cell line (NK3.3), and a population of murine NK cells can produce the type 2 cytokine IL-13 in response to IL-2 or phorbol myristate acetate plus ionomycin. IL-2 rapidly induced new IL-13 mRNA and protein synthesis in the NK3.3 cell line. Six of 12 human NK clones tested produced IL-13 protein in response to IL-2 or phorbol myristate acetate and ionomycin. Intracellular analysis revealed that ∼2% of human peripheral NK cells produced IL-13 protein in response to IL-2. Isolated NK cells from SCID and RAG-2 knockout (−/−) mice that lack T and B cells as well as normal mice also can produce IL-13 mRNA and protein in response to IL-2. We hypothesized that in the absence of IFN-γ, IL-13-producing NK cells may predominate in vivo. Utilizing IFN-γ knockout (−/−) mice as a model system, IL-2-activated liver NK and T cells expressed 10-fold more IL-13 and IL-5 mRNA and protein than normal controls following IL-2 treatment in vitro. These results suggest that in the absence of IFN-γ, an IL-13- and IL-5-producing NK and T cells predominate in vivo. The existence of this cell type has important implications in innate immunity given that the balance between IFN-γ and IL-13/IL-5-producing NK cells may influence the early development of a cell-mediated or humoral immune response.
Interaction of Sulfonamide Derivatives with the TCR of Sulfamethoxazole-Specific Human αβ+ T Cell Clones
Authors: von Greyerz Salome , Zanni Martin P. , Frutig Karin , Schnyder Benno , Burkhart Christoph , Pichler Werner J. 
Published: December 2022

AbstractDrugs like sulfamethoxazole (SMX) or lidocaine can be presented to specific human αβ+ T cell clones (TCC) by undergoing a noncovalent association with MHC-peptide complexes on HLA-matched APCs. For a better understanding of the molecular basis of the recognition of such drugs by specific TCC, we investigated 1) the fine specificity of the recognizing TCR, 2) the dose-response relationship for the induction of proliferation or cytokine production, and 3) the mechanism of TCR triggering. For that purpose, we tested the reactivity of 11 SMX-specific CD4+ TCC and 2 SMX-specific CD8+ TCC to a panel of 13 different sulfonamide derivatives bearing the same core structure. Five of 13 clones recognized only SMX, while all other clones were responding to as many as 6 different compounds. Some of the compounds needed up to two orders of magnitude higher concentrations than SMX to stimulate TCC, thereby displaying features of weak agonists. Different clones showed clear differences in the minimal drug concentration required for the induction of a proliferative response. Therefore, weaker or stronger agonistic properties were not a characteristic of a given sulfonamide derivative but rather an intrinsic property of the reacting TCR. Finally, the number of down-regulated TCRs was a logarithmic function of the ligand concentration, implicating that specific T cells were activated by serial TCR engagement. Our data demonstrate that, despite the special way of presentation, nonpeptide Ag like drugs appear to interact with the TCR of specific T cells in a similar way as peptide Ags.
Mice Lacking Mature T and B Lymphocytes Develop Arthritic Lesions after Immunization with Type II Collagen
Authors: Plows David , Kontogeorgos George , Kollias George 
Published: December 2022

AbstractCollagen-induced arthritis in DBA/1 mice is a widely used experimental model of rheumatoid arthritis. The induction phase of the disease is thought to be dependent upon MHC-restricted T and B cell-mediated immune responses to type II collagen, but an influence of additional non-MHC-restricted mechanisms has also been proposed. In this study, we report that type II collagen immunization of DBA/1 mice lacking mature T and B lymphocytes resulted in the development of arthritic lesions, which were characterized by synovial hyperplasia with occasional inflammation as well as cartilage and bone destruction. The specificity of disease induction to type II collagen was confirmed, because arthritis could not be induced when control preparations of OVA or adjuvant alone were administered. A delay in clinical disease onset and a reduction in severity between lymphocyte-positive and -negative DBA/1 mice confirmed that lymphocytes play an important role in disease; however, similar pathologic features and normal incidence suggest that lymphocyte-independent mechanisms of disease induction also operate in the standard collagen-induced arthritis model. We conclude that adaptive immune responses are not the only arthritogenic mechanism and hypothesize that the nonantigenic properties of type II collagen can also lead to arthritis.