bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Type II IL-1 Receptor Interacts with the IL-1 Receptor Accessory Protein: A Novel Mechanism of Regulation of IL-1 Responsiveness
Authors: Lang Detlef , Knop Johannes , Wesche Holger , Raffetseder Ute , Kurrle Roland , Boraschi Diana , Martin Michael U. 
Published: December 2022

AbstractIL-1 binds to two types of receptors on the cell membrane, of which only type I (IL-1RI) transduces signals in concert with the coreceptor IL-1 receptor accessory protein (IL-1RAcP) while type II (IL-1RII) allegedly functions solely as ligand sink and decoy receptor without participating in IL-1 signaling. To investigate the regulatory role of IL-1RII on IL-1 responsiveness, a chimeric receptor encompassing the extracellular and transmembrane portions of IL-1RII and the cytoplasmic signal-transducing domain of IL-1RI was transfected into two murine EL-4-derived sublines that do or do not express IL-1RAcP, respectively. The chimeric receptor was able to transduce the IL-1 signal and induce IL-2 production only in the cell line which expressed IL-1RAcP, suggesting effective interaction between the extracellular domains of IL-1RII and IL-1RAcP in the presence of IL-1. The physical association of ligated IL-1RII with IL-1RAcP was proven by crosslinking experiments with radio-iodinated IL-1 and subsequent immunoprecipitations in normal human B cells and in EL-4 D6/76 cells transiently cotransfected with IL-1RII and IL-1RAcP, respectively. Based on these findings, it is proposed that upon IL-1 binding IL-1RII can recruit IL-1RAcP into a nonfunctional trimeric complex and thus modulate IL-1 signaling by subtracting the coreceptor molecule from the signaling IL-1RI. In this novel mechanism of coreceptor competition, the ratio between IL-1RII and IL-1RI becomes the central factor in determining the IL-1 responsiveness of a cell and the availability of IL-1RAcP becomes limiting for effective IL-1 signaling.
Successful Induction of Adjuvant Arthritis in Mice by Treatment with a Monoclonal Antibody Against IL-4
Authors: Yoshino Shin , Murata Yuzo , Ohsawa Motoyasu 
Published: December 2022

AbstractAdjuvant arthritis (AA) is an experimental model of autoimmune disease in rats induced by immunization with Mycobacterium tuberculosis (MT). Induction of AA in other species, including mice, has been shown to be difficult. In the present study, we found that AA could be induced in mice if the animals were treated with a mAb (11B11 mAb) against IL-4. Histologically, the joints exhibited synovial edema with infiltration of many neutrophils in the early phase of inflammation. In its late phase, there were proliferation of synovium, cell infiltrate in which mononuclear cells predominated, and destruction of cartilage and subchondral bone. The joint inflammation was passively transferred to normal syngeneic recipient mice with lymphoid cells but not with sera from mice immunized with MT followed by treatment with the anti-IL-4 Ab. Delayed-type hypersensitivity (DTH) and proliferative responses of lymphoid cells to purified protein derivative were markedly augmented in 11B11 mAb-treated mice. Furthermore, the induction of arthritis was associated with a marked decrease in IL-4 secretion but a significant increase in IFN-γ and IL-2 production. Thus, the neutralization of IL-4 by an anti-IL-4 Ab appears to be required for the induction of AA in mice.
IL-4 Inhibits Mouse Mast Cell FcεRI Expression Through a STAT6-Dependent Mechanism
Authors: Ryan John J. , DeSimone Shirley , Klisch Gregory , Shelburne Christopher , McReynolds Lisa J. , Han Kathy , Kovacs Reka , Mirmonsef Paria , Huff Thomas F. 
Published: December 2022

AbstractMast cell activation by IgE-mediated stimuli is a central event in atopic disease. The regulation of the mast cell high affinity receptor, FcεRI, is poorly understood. We show that IL-4 can inhibit FcεRI expression on mouse bone marrow-derived mast cells and fetal liver-derived mast cell progenitors. This effect could be observed at 2.5 ng/ml IL-4 and was dose dependent. IL-4-mediated inhibition of cultured BMMC required 4 days of stimulation and was sustained at maximum levels for at least 21 days. The inhibition of FcεRI expression resulted in decreased sensitivity to IgE-mediated stimulation, as measured by serotonin release, and the induction of mRNA for IL-4, IL-5, IL-6, and IL-13. Additionally, IL-4 could abrogate the IgE-mediated increase in FcεRI expression. Lastly, IL-4-mediated inhibition was dependent upon expression of the STAT6 transcription factor, as STAT6-deficient bone marrow-derived mast cells did not decrease FcεRI levels in response to IL-4. These data argue for a homeostatic role of IL-4 in the regulation of FcεRI expression, a role that could be critical to understanding atopic disease.
Activation of Phosphatidylinositol 3-Kinase, Protein Kinase B, and p70 S6 Kinases in Lipopolysaccharide-Stimulated Raw 264.7 Cells: Differential Effects of Rapamycin, Ly294002, and Wortmannin on Nitric Oxide Production
Authors: Salh B. , Wagey R. , Marotta A. , Tao J. S. , Pelech S. 
Published: December 2022

AbstractPhosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B are critical players in cell proliferation and survival. Their downstream effector protein kinase, p70 S6 kinase, has an established role in protein translation. The mechanism by which bacterial LPS induces production of nitric oxide (NO) in murine macrophages is incompletely understood, and a role for PI 3-kinase/p70 S6 kinase pathway had not been previously investigated. In this study we demonstrate that LPS induced a fivefold activation of p70 S6 kinase and a twofold stimulation of PI 3-kinase. Pretreatment of Raw 264.7 cells with either rapamycin or Ly290042 completely blocked LPS-induced activation of p70 S6 kinase. Protein kinase B was also activated (twofold) by LPS and was only minimally affected by these inhibitors. PI 3-kinase activity was inhibited by both Ly294002 and wortmannin. The effects on NO production by these agents were strikingly different. While both rapamycin and Ly294002 resulted in almost complete inhibition of NO production, wortmannin was ineffective. Surprisingly, none of the inhibitors reduced the production of the inducible nitric oxide synthase protein (iNOS) as determined by immunoprecipitation. In vivo labeling studies revealed that the iNOS protein was phosphorylated in concordance with the production of NO. We conclude that LPS-mediated NO production occurs via a PI 3-kinase-independent, but FKBP12-rapamycin-associated protein-dependent, pathway in RAW cells by a mechanism probably involving phosphorylation of iNOS.
Environmental Antigen-Induced IL-13 Responses Are Elevated Among Subjects with Allergic Rhinitis, Are Independent of IL-4, and Are Inhibited by Endogenous IFN-γ Synthesis
Authors: Li Yan , Simons F. Estelle R. , HayGlass Kent T. 
Published: December 2022

AbstractHuman immediate hypersensitivity diseases represent the most common example of chronic excessive Th2-like activation in developed nations. While IL-13 shares many functional properties with IL-4, the intensity and regulation of environmental Ag-stimulated IL-13 synthesis by allergic vs nonallergic individuals remain ill defined. Here, we examine the intensity of polyclonally and Ag-stimulated IL-13 production by PBMC of 20 subjects with seasonal allergic rhinitis and 20 healthy controls. Polyclonally driven IL-13 responses did not differ significantly (Mann-Whitney U test, p = 0.68). In contrast, the median CD4-dependent IL-13 response among atopics was markedly stronger than nonatopics in Ag-stimulated primary culture (p = 0.0031) and exhibited a strong correlation with IL-5 (r = 0.76, p = 0.0009), but not IL-4 (r = 0.14, p &gt; 0.05), responses. IL-13 production was unaffected by blocking endogenous IL-4 or IL-5 activity or by addition of rIL-4 or rIL-5. In contrast, it was inhibited by low levels of rIFN-γ and strongly enhanced upon addition of neutralizing anti-IFN-γ mAb. Collectively, the data are consistent with a negative regulatory role for endogenous IFN-γ synthesis in controlling the intensity of systemic IL-13 responses evoked in both atopic and nonatopic populations following exposure to common Ags. They also suggest that the elevated levels of IL-4 and IL-5 characteristic of type 2-dominated responses in vivo are without detectable impact on the maintenance of recall Ag-stimulated IL-13 production.
Terminal Deoxynucleotidyl Transferase Deficiency Reduces the Incidence of Autoimmune Nephritis in (New Zealand Black × New Zealand White)F1 Mice
Authors: Conde Carmen , Weller Sandra , Gilfillan Susan , Marcellin Luc , Martin Thierry , Pasquali Jean-Louis 
Published: December 2022

AbstractTerminal deoxynucleotidyl transferase (TdT) enzyme activity in lymphocytes generates diversity in the Ag receptor repertoires by adding template-independent N nucleotides and disrupting homology-directed rearrangements. The importance of this diversity in vivo and the significance of the suppression of TdT during fetal life remain uncertain. Previous studies have shown that in TdT knockout mice (TdT°) 1) the T cell repertoire is less peptide oriented; and 2) natural autoantibody, particularly anti-DNA autoantibodies, are less polyreactive, and their mean affinities are reduced. Consequently, the suppression of TdT during early T/B cell ontogeny may participate in controlling autoimmunity. To study the impact of TdT suppression in autoimmune-prone mice, we introduced the TdT null mutation into the (NZB × NZW)F1 (B/W) mouse strain. We show that TdT deficiency significantly reduces the incidence of autoimmune nephritis and prolongs survival compared with those in control mice. Surprisingly, the long-term survivor TdT° mice produced amounts of anti-ADN and anti-histone autoantibodies similar to those of their TdT+ littermates. However, these TdT° mice showed no evidence of renal inflammation, and the immune deposits were restricted to the mesangium, whereas basal membrane deposits were clearly correlated with overt renal disease. The present study supports the idea that the absence of TdT enzyme activity in lymphocytes protects mice against autoimmunity and could offer a therapeutic approach to autoimmune diseases. Moreover, our results may help to unravel the mechanisms of lupus nephritis.
Temporal Role of Chemokines in a Murine Model of Cockroach Allergen-Induced Airway Hyperreactivity and Eosinophilia
Authors: Campbell Emma M. , Kunkel Steven L. , Strieter Robert M. , Lukacs Nicholas W. 
Published: December 2022

AbstractThe increase in inner-city asthma among children appears to be due to allergic responses to several allergens. Recent studies have demonstrated that Ags derived from cockroaches are especially prominent in these settings and a significant health concern for the induction of asthma in children. In the present study, we have outlined the development of a murine model of cockroach allergen-induced airway disease and assessed specific mechanisms of the response, which resembles atopic human asthma. The allergic responses in this model include allergen-specific airway eosinophilia and significantly altered airway physiology, which directly correlates with inflammation. We have further utilized this allergen to establish primary and secondary rechallenge stages of late phase hyperreactivity exacerbation. This latter stage is characterized by greater changes in airway physiology than the primary stage, and it is likely due to the preexisting peribronchial inflammation present at the time of the second allergen rechallenge. We have identified specific roles for CC chemokines during these stages, with MIP-1α being an important eosinophil attractant during the primary stage and eotaxin during the secondary rechallenge stage. The development of these models allows the evaluation of mediators involved in both stages of cockroach allergen challenge, as well as the testing of specific therapeutic modalities.
Cutting Edge: Transcutaneous Immunization with Cholera Toxin Protects Mice Against Lethal Mucosal Toxin Challenge
Authors: Glenn Gregory M. , Scharton-Kersten Tanya , Vassell Russell , Mallett Corey P. , Hale Thomas L. , Alving Carl R. 
Published: December 2022

AbstractWe recently reported that application of cholera toxin (CT) to the skin results in transcutaneous immunization and induces a systemic Ab response to both CT and coadministered Ags. In this paper, we demonstrate antitoxin IgG and IgA Abs in sera, lung washes, and stool samples from immunized mice as well as a broad spectrum of IgG subclasses (IgG1, IgG2a, IgG2b, and IgG3) in the sera. Mice immunized with CT by the transcutaneous route exhibited significant protection from intranasal challenge with a lethal dose of CT. Thus, clinically relevant immunity against mucosal toxin challenge can be achieved via the transcutaneous route.
Identification of a Cytoplasmic Region of CD20 Required for Its Redistribution to a Detergent-Insoluble Membrane Compartment
Authors: Polyak Maria J. , Tailor Sweta H. , Deans Julie P. 
Published: December 2022

AbstractCD20 is a B lymphocyte integral membrane protein with signal-transducing properties. Abs directed toward extracellular CD20 epitopes activate nonreceptor tyrosine kinases and modulate cell cycle progression of B lymphocytes. Recently, we demonstrated that binding of CD20 Abs to B cells induces the rapid redistribution of up to 95% of CD20 molecules to low density, detergent-insoluble membrane microdomains and induces the appearance of an approximately 50-kDa tyrosine-phosphorylated protein in the same compartment. Active relocalization of CD20 may thus be critical to the initiation of signaling events by CD20. The CD20 cDNA sequence predicts a nonglycosylated protein with four transmembrane-spanning regions and intracellular amino and carboxyl termini. Here we provide verification of the location of both the intracellular and extracellular regions of the CD20 molecule and identify a membrane-proximal sequence in the cytoplasmic carboxyl tail that is required for CD20 to redistribute to detergent-insoluble membrane microdomains.
Generation of Biologically Active IL-1β by Matrix Metalloproteinases: A Novel Caspase-1-Independent Pathway of IL-1β Processing
Authors: Schönbeck Uwe , Mach François , Libby Peter 
Published: December 2022

AbstractBiologic activity of IL-1β requires processing of the inactive precursor, a function generally ascribed to IL-1β-converting enzyme (caspase-1). However, alternative mechanisms of IL-1β activation have been postulated in local inflammatory reactions. Expression of IL-1β and matrix metalloproteinases (MMPs) frequently occurs simultaneously at sites of inflammation. We describe here that stromelysin-1 (MMP-3), as well as the gelatinases A (MMP-2) and B (MMP-9), processes recombinant human IL-1β precursor (pIL-1β) into biologically active forms. Detection of both pIL-1β processing and biologic IL-1β activity demonstrated different processing capacities of the respective MMPs. Conversion of pIL-1β by stromelysin-1 required coincubation for at least 1 h, and biologic activity faded after 8 h to 24 h. Gelatinase A was less effective in processing pIL-1β, requiring at least 24 h of coincubation. In contrast, gelatinase B processed pIL-1β within minutes, resulting in immunoreactive products as well as biologic activity stable for 72 h. In addition, prolonged incubation of mature IL-1β with stromelysin-1, and to a lesser extent also with gelatinases, but not with interstitial collagenase, resulted in the degradation of mature IL-1β. None of the MMPs processed the second isoform of IL-1, IL-1α. The present study indicates a biphasic regulation of IL-1β activity by MMPs: a caspase-1-independent pathway of IL-1β activation and inhibition of IL-1β activity by degrading the mature cytokine. The balance of the respective MMPs and pIL-1β might regulate the long term appearance of IL-1β activity at sites of acute or chronic inflammation.
Steroid Hormone Regulation of Cytokine Secretion by Proteolipid Protein-Specific CD4+ T Cell Clones Isolated from Multiple Sclerosis Patients and Normal Control Subjects
Authors: Correale Jorge , Arias Magdalena , Gilmore Wendy 
Published: December 2022

AbstractSteroid hormones have long been known to modulate immune function, and recent studies indicate that one of the means by which they do so involves effects on the secretion of immunoregulatory cytokines. Our laboratory has found recently that estradiol (E2) selectively modifies cytokine secretion in proteolipid protein (PLP)-specific, CD4+ T cell clones isolated from patients with the demyelinating disease, multiple sclerosis, and from normal control subjects. The data suggest that E2 may play a role in regulating the balance between pro- and antiinflammatory conditions, especially at concentrations typical of pregnancy. To determine whether other pregnancy-associated steroid hormones are capable of similar activity, we expanded our testing to include estrone (E1), estriol (E3), progesterone, and dexamethasone. The results indicate that E1 and E3 enhance secretion of Ag- or anti-CD3-stimulated IL-10 and IFN-γ in dose-dependent fashion, almost identical to that of E2. The effect on IL-10 was more potent than occurred with IFN-γ. In addition, E1 and E3, like E2, had a biphasic effect on TNF-αβ secretion, with low concentrations stimulatory, and high doses inhibitory. None of the estrogens influenced IL-4 or TGF-β secretion. Progesterone enhanced secretion of IL-4, without affecting any other tested cytokine. Finally, dexamethasone induced TGF-β secretion, but inhibited IFN-γ and TNF-αβ. This differential effect of steroid hormones on the secretion of cytokines by CD4+ human T cell clones is consistent with the possibility that, collectively, they promote antiinflammatory conditions at high concentrations typical of pregnancy.
Selective Inhibitors of Cytosolic or Secretory Phospholipase A2 Block TNF-Induced Activation of Transcription Factor Nuclear Factor-κB and Expression of ICAM-1
Authors: Thommesen Liv , Sjursen Wenche , Gåsvik Kathrine , Hanssen Wenche , Brekke Ole-Lars , Skattebøl Lars , Holmeide Anne Kristin , Espevik Terje , Johansen Berit , Lægreid Astrid 
Published: December 2022

Abstract
TNF signaling mechanisms involved in activation of transcription factor NF-κB were studied in the human keratinocyte cell line HaCaT. We show that TNF-induced activation of NF-κB was inhibited by the well-known selective inhibitors of cytosolic phospholipase A2 (cPLA2): the trifluoromethyl ketone analogue of arachidonic acid (AACOCF3) and methyl arachidonyl fluorophosphate. The trifluoromethyl ketone analogue of eicosapentaenoic acid (EPACOCF3) also suppressed TNF-induced NF-κB activation and inhibited in vitro cPLA2 enzyme activity with a similar potency as AACOCF3. The arachidonyl methyl ketone analogue (AACOCH3) and the eicosapentanoyl analogue (EPACHOHCF3), which both failed to inhibit cPLA2 enzyme activity in vitro, had no effect on TNF-induced NF-κB activation. TNF-induced NF-κB activation was also strongly reduced in cells stimulated in the presence of the secretory PLA2 (sPLA2) inhibitors 12-epi-scalaradial and LY311727. Addition of excess arachidonic acid suppressed the inhibitory effect of 12-epi-scalaradial and LY311727. Moreover, both methyl arachidonyl fluorophosphate and 12-epi-scalaradial blocked TNF-mediated enhancement of expression of ICAM-1. Activation of NF-κB by IL-1β was markedly less sensitive to both cPLA2 and sPLA2 inhibitors. The results indicate that both cPLA2 and sPLA2 may be involved in the TNF signal transduction pathway leading to nuclear translocation of NF-κB and to NF-κB-activated gene expression in HaCaT cells.
Oxidant Stress Incites Spreading of Macrophages via Extracellular Signal-Regulated Kinases and p38 Mitogen-Activated Protein Kinase
Authors: Ogura Makoto , Kitamura Masanori 
Published: December 2022

AbstractCultured macrophages exhibit spreading in response to external stimuli. It is relevant to in vivo morphologic changes of macrophages during extravasation, migration, and differentiation. The present study was performed to elucidate molecular mechanisms that regulate spreading of macrophages. Redox is a crucial factor that modulates a wide range of cell function. We found that macrophages undergo spreading in response to oxidant stress caused by hydrogen peroxide or an oxidant generating agent menadione. To identify signaling pathways involved, a role of mitogen-activated protein (MAP) kinases was investigated. Western blot analysis showed that treatment of macrophages with menadione rapidly induced phosphorylation of extracellular signal-regulated kinases (ERK1, ERK2) and p38 MAP kinase, but not c-Jun N-terminal kinase (JNK). Pharmacologic inhibition of either ERK or p38 activation blunted the macrophage spreading. Similarly, transfection with dominant-negative mutants of ERKs or a mutant p38 significantly suppressed the oxidant-triggered spreading. ERKs and p38 are known to activate serum response element (SRE) via phosphorylation of the ternary complex factor Elk-1. To further identify downstream events, we focused on a role of SRE. Stimulation of macrophages with menadione induced activation of SRE. Intervention in the SRE activation by a dominant-negative mutant of Elk-1 inhibited the menadione-induced spreading. These results suggest that oxygen radical metabolites, the well-known mediators for tissue injury, incite spreading of macrophages via the MAP kinase-SRE signaling pathways.
A Breast and Melanoma-Shared Tumor Antigen: T Cell Responses to Antigenic Peptides Translated from Different Open Reading Frames
Authors: Wang Rong-Fu , Johnston Samuel L. , Zeng Gang , Topalian Suzanne L. , Schwartzentruber Douglas J. , Rosenberg Steven A. 
Published: December 2022

AbstractInfusion of TIL586 along with IL-2 into the autologous patient with metastatic melanoma resulted in the objective regression of tumor. Here, we report that screening a cDNA library from the 586mel cell line using CTL clones derived from TIL586 resulted in the isolation of a gene, CAG-3 (cancer Ag gene 3). Sequence analysis revealed that CAG-3 encodes an open reading frame identical to NY-ESO-1, which was recently reported to be recognized by autologous serum from a patient with esophageal cancer. Thus, NY-ESO-1 appears to be an immune target for both Ab- and T cell-mediated responses. Significantly, NY-ESO-1-specific CTL clones were capable of recognizing two HLA-A31-positive fresh and cultured breast tumors. To our knowledge, this represents the first direct demonstration that tumor-specific CTL clones can recognize both breast and melanoma tumor cells. A 10-mer antigenic peptide ESO10–53 (ASGPGGGAPR) was identified from the normal open reading frame of NY-ESO-1 based on its ability to sensitize HLA-A31-positive target cells for cytokine release and specific lysis. Interestingly, two additional CTL clones that were sensitized with NY-ESO-1 recognized two overlapping antigenic peptides derived from an alternative open reading frame of the same gene. These findings indicate that CTLs simultaneously responded to two different gene products translated from the normal and alternative reading frames of the same gene. Understanding of this mechanism by which the alternative reading frame is translated may have important implications in tumor immunology.