bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of CD44 Induction by IL-1: A Critical Role for Egr-1
Authors: Fitzgerald Katherine A. , O’Neill Luke A. J. 
Published: January 2023

Abstract
The adhesion molecule CD44 is a multifunctional, ubiquitously expressed glycoprotein that participates in the process of leukocyte recruitment to sites of inflammation and to their migration through lymphatic tissues. In this study, we have investigated the effect of the proinflammatory cytokine IL-1α on CD44 gene expression in the human immortalized endothelial cell line ECV304. Immunoblotting of cell extracts showed constitutive expression of a 85-kDa protein corresponding to the standard form of CD44, which was potently up-regulated following IL-1α treatment. Furthermore, IL-1α induced expression of v3- and v6-containing isoforms of CD44, which migrated at 110 and 140–180 kDa, respectively. The effect of IL-1α on CD44 standard, v3- and v6-containing isoforms was dose and time dependent and was inhibited in the presence of IL-1 receptor antagonist. To elucidate the molecular mechanisms regulating CD44 expression in response to IL-1α, we investigated the effect of IL-1α on CD44 mRNA expression. Reverse-transcriptase PCR and Northern analysis demonstrated an increase in CD44 mRNA expression indicating a transcriptional mechanism of control by IL-1α. Furthermore, IL-1α increased expression of a reporter gene under the control of the CD44 promoter (up to −1.75 kb). The effect of IL-1α was critically dependent on the site spanning −151 to −701 of the promoter. This effect required the presence of an Egr-1 motif at position −301 within the CD44 promoter since mutation of this site abolished responsiveness. IL-1α also induced Egr-1 expression in these cells. These studies therefore identify Egr-1 as a critical transcription factor involved in CD44 induction by IL-1α.
Role of TGF-β1 on the IgE-Dependent Anaphylaxis Reaction
Authors: Kim Hyung-Min , Lee Young-Mi 
Published: January 2023

Abstract
TGF-β1 is a member of a family of polypeptide factors that control proliferation, differentiation, chemotaxis, and other functions in many cell types. TGF-β1 has been shown to inhibit many immunologic functions. However, here we report that TGF-β1 has an important role in the elicitation of IgE-dependent allergic reactions. The synthetic antisense TGF-β1 oligonucleotides dose-dependently inhibit passive cutaneous anaphylaxis (PCA) reaction and histamine release from the mast cells activated by anti-DNP IgE in rats. The level of cAMP in mast cells, when antisense TGF-β1 oligonucleotides was added, significantly increased ∼7-fold compared with that of basal cells. The antisense TGF-β1 oligonucleotides also had a significant inhibitory effect on anti-DNP IgE-induced TNF-α release from mast cells. In situ hybridization analysis showed that the PCA reaction sites treated with antisense TGF-β1 oligonucleotides exhibited no detectable levels of TGF-β1 and l-histidine decarboxylase mRNA after anti-DNP IgE stimulation, whereas the PCA reaction sites treated with sense TGF-β1 oligonucleotides possessed significant amounts of their mRNA. Additionally, neutralizing Ab to TGF-β1 blocked the PCA reaction significantly, but its Ab did not inhibit peritoneal mast cell-released histamine upon treatment with anti-DNP IgE. Our results suggest that TGF-β1 is critical to the development of IgE-dependent anaphylaxis reactions.
Cutting Edge: Proteasome Involvement in the Degradation of Unassembled Ig Light Chains
Authors: O’Hare Thomas , Wiens Gregory D. , Whitcomb Elizabeth A. , Enns Caroline A. , Rittenberg Marvin B. 
Published: January 2023

Abstract
Several studies on disposal of nonsecreted Ig L chains have identified the endoplasmic reticulum as the site of degradation. Here, we examine degradation of a nonsecreted Ig L chain, T15L, and an experimentally endoplasmic reticulum-retained secretion-competent L chain, D16L, in the absence of H chains. We demonstrate that 1) degradation is specifically impaired by the proteasome-specific inhibitors carboxybenzyl-leucyl-leucyl-leucine vinyl sulfone (Z-L3VS) and lactacystin, 2) L chain degradation occurs early in the biosynthetic pathway, and 3) degradation does not require vesicular transport. Our findings indicate that previous assertions of L chain disposal within the endoplasmic reticulum must be modified. To our knowledge, we provide the first direct evidence supporting a new paradigm for removal of nonsecreted Ig L chains via dislocation to cytosolic proteasomes.
IFN-γ- and Cell-to-Cell Contact-Dependent Cytotoxicity of Allograft-Induced Macrophages Against Syngeneic Tumor Cells and Cell Lines: An Application of Allografting to Cancer Treatment
Authors: Yoshida Ryotaro , Yoneda Yukio , Kuriyama Manabu , Kubota Takahiro 
Published: January 2023

Abstract
In allogeneic tumor or skin transplantation, the rejection process that destroys the allogeneic cells leaves syngeneic cells intact by discrimination between self and nonself. Here, we examined whether the cells infiltrating into the allografts could be cytotoxic against syngeneic immortal cells in vitro and in vivo. The leukocytes (i.e., macrophages (Mφ; 55–65% of bulk infiltrates), granulocytes (20–25%), and lymphocytes (15–20%)) infiltrating into allografts, but not into autografts, in C57BL/6 mice were cytotoxic against syngeneic tumor cells and cell lines, whereas the cytotoxic activity was hardly induced in allografted, IFN-γ−/− C57BL/6 mice. Among the leukocytes, Mφ were the major population of cytotoxic cells; and the cytotoxic activity appeared to be cell-to-cell contact dependent. When syngeneic tumor cells were s.c. injected into normal C57BL/6 mice simultaneously with the Mφ-rich population or allogeneic, but not syngeneic, fibroblastic cells, tumor growth was suppressed in a cell number-dependent manner, and tumor cells were rejected either with a Mφ:tumor ratio of about 30 or with an allograft:tumor ratio of ∼200. In the case of IFN-γ−/− C57BL/6 mice, however, the s.c. injection of the allograft simultaneously with tumor cells had no effect on the tumor growth. These results suggest that allograft or allograft-induced Mφ may be applicable for use in cancer treatment and that IFN-γ induction by the allograft may be crucial for the treatment.
Transfection of Immature Murine Bone Marrow-Derived Dendritic Cells with the Granulocyte-Macrophage Colony-Stimulating Factor Gene Potently Enhances Their In Vivo Antigen-Presenting Capacity
Authors: Curiel-Lewandrowski Clara , Mahnke Karsten , Labeur Marta , Roters Berthold , Schmidt Walter , Granstein Richard D. , Luger Thomas A. , Schwarz Thomas , Grabbe Stephan 
Published: January 2023

AbstractAg presentation by dendritic cells (DC) is crucial for induction of primary T cell-mediated immune responses in vivo. Because DC culture from blood or bone marrow-derived progenitors is now clinically applicable, this study investigated the effectiveness of in vitro-generated murine bone marrow-derived DC (Bm-DC) for in vivo immunization protocols. Previous studies demonstrated that GM-CSF is an essential growth and differentiation factor for DC in culture and that in vivo administration of GM-CSF augments primary immune responses, which renders GM-CSF an attractive candidate to further enhance the effectiveness of DC-based immunotherapy protocols. Therefore, immature Bm-DC were transiently transfected with the GM-CSF gene and tested for differentiation, migration, and Ag-presenting capacity in vitro and in vivo. In vitro, GM-CSF gene-transfected Bm-DC were largely unaltered with regard to MHC and costimulatory molecule expression as well as alloantigen or peptide Ag-presenting capacity. When used for in vivo immunizations, however, the Ag-presenting capacity of GM-CSF gene-transfected Bm-DC was greatly enhanced compared with mock-transfected or untransfected cells, as determined by their effectiveness to induce primary immune reactions against hapten, protein Ag, and tumor Ag, respectively. Increased effectiveness in vivo correlated with the better migratory capacity of GM-CSF gene-transfected Bm-DC. These results show that GM-CSF gene transfection significantly enhances the capacity of DC to induce primary immune responses in vivo, which might also improve DC-based vaccines currently under clinical investigation.
A Model for CD8+ CTL Tumor Immunosurveillance and Regulation of Tumor Escape by CD4 T Cells Through an Effect on Quality of CTL
Authors: Matsui So , Ahlers Jeffrey D. , Vortmeyer Alex O. , Terabe Masaki , Tsukui Taku , Carbone David P. , Liotta Lance A. , Berzofsky Jay A. 
Published: January 2023

Abstract
Understanding immune mechanisms influencing cancer regression, recurrence, and metastasis may be critical to developing effective immunotherapy. Using a tumor expressing HIV gp160 as a model viral tumor Ag, we found a growth-regression-recurrence pattern, and used this to investigate mechanisms of immunosurveillance. Regression was dependent on CD8 T cells, and recurrent tumors were resistant to CTL, had substantially reduced expression of epitope mRNA, but retained the gp160 gene, MHC, and processing apparatus. Increasing CTL numbers by advance priming with vaccinia virus expressing gp160 prevented only the initial tumor growth but not the later appearance of escape variants. Unexpectedly, CD4 cell depletion protected mice from tumor recurrence, whereas IL-4 knockout mice, deficient in Th2 cells, did not show this protection, and IFN-γ knockout mice were more susceptible. Purified CD8 T cells from CD4-depleted mice following tumor regression had more IFN-γ mRNA and lysed tumor cells without stimulation ex vivo, in contrast to CD4-intact mice. Thus, the quality as well as quantity of CD8+ CTL determines the completeness of immunosurveillance and is controlled by CD4 T cells but not solely Th2 cytokines. This model of immunosurveillance may indicate ways to enhance the efficacy of surveillance and improve immunotherapy.
Genes Encoding Three New Members of the Leukocyte Antigen 6 Superfamily and a Novel Member of Ig Superfamily, Together with Genes Encoding the Regulatory Nuclear Chloride Ion Channel Protein (hRNCC) and aNω-Nω-Dimethylarginine Dimethylaminohydrolase Homologue, Are Found in a 30-kb Segment of the MHC Class III Region
Authors: Ribas Gloria , Neville Matt , Wixon Joanne L. , Cheng Jianhua , Campbell R. Duncan 
Published: January 2023

AbstractMany of the genes in the class III region of the human MHC encode proteins involved in the immune and inflammatory responses. We have sequenced a 30-kb segment of the MHC class III region lying between the heat shock protein 70 and TNF genes as part of a program aimed at identifying genes that could be involved in autoimmune disease susceptibility. The sequence analysis has revealed the localization of seven genes, whose precise position and order is cen-G7-G6-G6A-G6B-G6C-G6D-G6E-tel, five of which are fully encoded in the sequence, allowing their genomic structures to be defined. Three of them (G6C, G6D, and G6E) encode putative proteins that belong to the Ly-6 superfamily, known to be GPI-anchored proteins attached to the cell surface. Members of the family are specifically expressed and are important in leukocyte maturation. A fourth gene, G6B, encodes a novel member of the Ig superfamily containing a single Ig V-like domain and a cytoplasmic tail with several signal transduction features. The G6 gene encodes a regulatory nuclear chloride ion channel protein, while the G6A gene encodes a putative homologue of the enzyme Nω,Nω-dimethylarginine dimethylaminohydrolase, which is thought to be involved in regulating nitric oxide synthesis. In addition, three microsatellite markers, 9N-1, 82-2, and D6S273 are contained within the sequence, the last two of which have been reported to be strongly associated with the autoimmune disease ankylosing spondylitis.
Differential Cytokine Modulation and T Cell Activation by Two Distinct Classes of Thalidomide Analogues That Are Potent Inhibitors of TNF-α
Authors: Corral Laura G. , Haslett Patrick A. J. , Muller George W. , Chen Roger , Wong Lu-Min , Ocampo Christopher J. , Patterson Rebecca T. , Stirling David I. , Kaplan Gilla 
Published: January 2023

Abstract
TNF-α mediates both protective and detrimental manifestations of the host immune response. Our previous work has shown thalidomide to be a relatively selective inhibitor of TNF-α production in vivo and in vitro. Additionally, we have recently reported that thalidomide exerts a costimulatory effect on T cell responses. To develop thalidomide analogues with increased anti-TNF-α activity and reduced or absent toxicities, novel TNF-α inhibitors were designed and synthesized. When a selected group of these compounds was examined for their immunomodulatory activities, different patterns of cytokine modulation were revealed. The tested compounds segregated into two distinct classes: one class of compounds, shown to be potent phosphodiesterase 4 inhibitors, inhibited TNF-α production, increased IL-10 production by LPS-induced PBMC, and had little effect on T cell activation; the other class of compounds, similar to thalidomide, were not phosphodiesterase 4 inhibitors and markedly stimulated T cell proliferation and IL-2 and IFN-γ production. These compounds inhibited TNF-α, IL-1β, and IL-6 and greatly increased IL-10 production by LPS-induced PBMC. Similar to thalidomide, the effect of these agents on IL-12 production was dichotomous; IL-12 was inhibited when PBMC were stimulated with LPS but increased when cells were stimulated by cross-linking the TCR. The latter effect was associated with increased T cell CD40 ligand expression. The distinct immunomodulatory activities of these classes of thalidomide analogues may potentially allow them to be used in the clinic for the treatment of different immunopathological disorders.
Myelin Oligodendrocyte Glycoprotein Induces Experimental Autoimmune Encephalomyelitis in the “Resistant” Brown Norway Rat: Disease Susceptibility Is Determined by MHC and MHC-Linked Effects on the B Cell Response
Authors: Stefferl Andreas , Brehm Uschi , Storch Maria , Lambracht-Washington Doris , Bourquin Carole , Wonigeit Kurt , Lassmann Hans , Linington Christopher 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis (EAE) induced by active immunization with the myelin oligodendrocyte glycoprotein (MOG) is an Ab-mediated, T cell-dependent autoimmune disease that replicates the inflammatory demyelinating pathology of multiple sclerosis. We report that disease susceptibility and severity are determined by MHC and MHC-linked effects on the MOG-specific B cell response that mediate severe clinical EAE in the EAE-resistant Brown Norway (BN) rat. Immunization with the extracellular domain of MOG in CFA induced fulminant clinical disease associated with widespread demyelination and with an inflammatory infiltrate containing large numbers of polymorphonuclear cells and eosinophils within 10 days of immunization. To analyze the effects of the MHC (RT1 system) we compared BN (RT1 n) rats with Lewis (LEW) (RT1 l) and two reciprocal MHC congenic strains, LEW.1N (RT1n) and BN.1L (RT1 l). This comparison revealed that disease severity and clinical course were strongly influenced by the MHC haplotype that modulated the pathogenic MOG-specific autoantibody response. The intra-MHC recombinant congenic strain LEW.1R38 demonstrated that gene loci located both within the centromeric segment of the MHC containing classical class I and class II genes and within the telomeric RT1.M region containing the MOG gene are involved in determining Ab production and disease susceptibility. This study indicates that the current T cell-centered interpretation of MHC-mediated effects on disease susceptibility must be reassessed in multiple sclerosis and other autoimmune diseases in which autoantibody is involved in disease pathogenesis.
The Murine Antiapoptotic Protein A1 Is Induced in Inflammatory Macrophages and Constitutively Expressed in Neutrophils
Authors: Orlofsky Amos , Somogyi Robert D. , Weiss Louis M. , Prystowsky Michael B. 
Published: January 2023

Abstract
Myeloid leukocytes are thought to regulate their susceptibility to apoptosis upon migration to a site of inflammation. However, factors that determine survival have not been well characterized in these cells. We have examined the expression of murine A1, an antiapoptotic Bcl-2 relative found in activated myeloid cells, during the course of an acute inflammatory response. Intraperitoneal infection of mice with the virulent RH strain of Toxoplasma gondii led to a 5- to 10-fold increase in A1 mRNA levels in peritoneal cells after several days. Bcl-2 expression was unchanged. The increase in A1 expression depended on the dose of the organism and coincided with a sharp increase in peritoneal cellularity. A1 protein levels were also increased as determined by Western blot analysis and immunohistochemical studies. All neutrophils and approximately half of the macrophages in the inflammatory exudate contained high levels of A1 in cytoplasm. A1 expression did not correlate with intracellular parasitization. Peripheral blood neutrophils from normal mice strongly expressed A1 protein, whereas normal monocytes showed only weak staining. Bax mRNA was induced in parallel with A1 in macrophages. Exudate macrophages and granulocytes that were apoptotic by TUNEL staining occasionally appeared to display A1 throughout the cell nucleus. These studies identify A1 as a potential regulator of apoptosis during acute inflammation.
Repeated Administration of Adenoviral Vectors in Lungs of Human CD4 Transgenic Mice Treated with a Nondepleting CD4 Antibody
Authors: Chirmule Narendra , Truneh Alemseged , Haecker Sarah Ehlen , Tazelaar John , Gao Guang-ping , Raper Steven E. , Hughes Joseph V. , Wilson James M. 
Published: January 2023

Abstract
The central role of CD4+ T cells in regulation of adenovirus vector-mediated immune responses has been documented previously in murine models. We analyzed the effects of a nondepleting mAb to human CD4 (CD4 mAb; Clenoliximab) on immune functions following intratracheal administration of adenoviral vectors in murine CD4-deficient mice (muCD4KO) expressing a human CD4 transgene (HuCD4 mice). Treatment of HuCD4 mice with Clenoliximab inhibited both cell-mediated and humoral immune responses to adenoviral Ags. Chronic treatment of HuCD4 mice with Clenoliximab permitted successful readministration of adenoviral vectors at least four times. The ability to readminister these vectors is associated with marked suppression of neutralizing Ab responses to viral capsid proteins. Clenoliximab also inhibited CTL and prolonged expression of the transgene. T or B cell responses to adenovirus did not emerge after the effects of a short course of Clenoliximab diminished. These data illustrate the potential utility of a nondepleting CD4 Ab in facilitating gene therapy using adenoviral vectors.
Differential Role for p38 Mitogen-Activated Protein Kinase in Regulating CD40-Induced Gene Expression in Dendritic Cells and B Cells
Authors: Aicher Alexandra , Shu Geraldine L. , Magaletti Dario , Mulvania Thera , Pezzutto Antonio , Craxton Andrew , Clark Edward A. 
Published: January 2023

AbstractWe investigated whether human monocyte-derived dendritic cells (DCs) differed from tonsillar B cells in the set of cell fate genes they express constitutively and in the way these genes are affected after CD40 ligation. In particular, Bcl-2, TNF receptor-associated factor-2 (TRAF2), and TRAF4 were clearly inducible via CD40 in B cells but not in DCs. DCs, unlike B cells, were induced to increase expression of IL-1β, IL-1Ra, IL-8, IL-12 p40, RANTES, macrophage inflammatory protein-1α, and monocyte chemoattractant protein-1 after CD40 ligation. We next tested whether CD40-induced signaling pathways were different in DCs vs B cells. In DCs, as in B cells, CD40 ligation activated p38 mitogen-activated protein kinase (MAPK), its downstream target, MAPKAPK-2, and the c-Jun N-terminal kinase. The p38 MAPK-specific inhibitor, SB203580, blocked CD40-induced MAPKAPK-2 activation, but did not affect activation of c-Jun N-terminal kinase. Furthermore, unlike in B cells, extracellular signal-regulated kinase-1 and -2 were activated after CD40 ligation in DCs. SB203580 strongly blocked CD40-induced IL-12 p40 production in DCs at both mRNA and protein levels, while having minimal effect on CD40-induced expression of the chemokine RANTES. In contrast, no detectable IL-12 p40 protein was secreted in CD40-stimulated B cells. Furthermore, CD40-induced mRNA expression of cellular inhibitor of apoptosis protein-2 was also dependent on the p38 MAPK pathway in DCs and differed compared with that in B cells. In conclusion, CD40 induces distinct programs in DCs and B cells, and the set of p38 MAPK-dependent genes in DCs (IL-12 p40 and cellular inhibitor of apoptosis protein-2) is different from that in B cells (IL-10 and IL-1β).
Phosphorothioate Oligodeoxynucleotides Promote the In Vitro Development of Human Allergen-Specific CD4+ T Cells into Th1 Effectors
Authors: Parronchi Paola , Brugnolo Francesca , Annunziato Francesco , Manuelli Cinzia , Sampognaro Salvatore , Mavilia Carmelo , Romagnani Sergio , Maggi Enrico 
Published: January 2023

AbstractDNA vaccination is an effective approach in inducing the switch of murine immune responses from a Th2 to a Th1 profile of cytokine production that has been related to the activity of unmethylated CpG motifs present in bacterial, but not mammalian, DNA. We report here that some synthetic phosphorothioate, but not phosphodiester, oligodeoxynucleotides (ODNs) were able to induce B cell proliferation and to shift the in vitro differentiation of Dermatophagoides pteronyssinus group 1-specific human CD4+ T cells from atopic donors into Th cell effectors showing a prevalent Th1, instead of Th2, cytokine profile. This latter effect was completely blocked by the neutralization of IL-12 and IFN (α and γ) in bulk culture, suggesting that the Th1-inducing activity of phosphorothioate ODNs was mediated by their ability to stimulate the production of these cytokines by monocytes, dendritic, and NK cells. Cytosine methylation abolished the Th1-inducing activity of ODNs; however, CpG dinucleotide-containing ODNs exhibited the Th1-shifting effect independently of the presence or the absence of CpG motifs (5′-pur-pur-CpG-pyr-pyr-3′). Moreover, the inversion of CpG to GpC resulted only in a partial reduction of this activity, suggesting that the motif responsible for the Th1-skewing effect in humans is at least partially different from that previously defined in mice. These results support the concept that the injection of allergens mixed to, or conjugated with, appropriate ODNs may provide a novel allergen-specific immunotherapeutic regimen for the treatment of allergic disorders.