bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of IL-4-mediated suppression of IP-10 gene expression in murine macrophages.
Authors: Deng W , Ohmori Y , Hamilton T A 
Published: December 2022

Abstract
The mechanisms involved in negative regulation of IFN-gamma-induced IP-10 mRNA expression by IL-4 have been examined in an immortalized murine macrophage cell line (ANA-1). As in primary peritoneal macrophages, IL-4 selectively inhibits the production of IP-10 mRNA by IFN-gamma-treated ANA-1 cells. Expression of another IFN-gamma-inducible gene (D3) was not affected by co-treatment with IL-4. Suppression of IFN-gamma-induced IP-10 mRNA expression by IL-4 is mediated at the level of transcription. IFN-gamma-induced transcription of CAT expression driven by a 243-bp IP-10 promoter fragment was also sensitive to the suppressive effects of IL-4. In contrast, LPS-induced CAT expression was unaffected under identical experimental conditions. The positive transcriptional response to IFN-gamma required an interferon stimulus response element (ISRE) sequence motif located approximately 230 bp upstream from the transcription start site of the IP-10 gene. That this site is the target of the suppressive action of IL-4 is indicated by the ability of IL-4 to inhibit IFN-gamma-mediated transcription from this ISRE sequence in the context of a heterologous promoter. Finally, both IFN-gamma and IL-4 can enhance or induce expression of distinct nuclear factors that exhibit ISRE-specific binding activity. IL-4 does not suppress the IFN-gamma-induced ISRE binding activity. Together, these findings demonstrate that IL-4 inhibits IP-10 mRNA production in murine macrophages by suppressing the formation of new transcripts. Both positive and negative transcriptional activity appears dependent on activation of factors that recognize the ISRE.
Different signaling pathways for CD18-mediated adhesion and Fc-mediated phagocytosis. Response of neutrophils to LPS.
Authors: Detmers P A , Zhou D , Powell D E 
Published: December 2022

Abstract
The regulation of CD11b/CD18 adhesive and phagocytic functions on human polymorphonuclear leukocytes (PMN) in response to LPS was examined. Adhesion of PMN to surfaces coated with LPS had little or no effect on the cells, but pretreating the LPS-coated surfaces with either diluted serum or LPS-binding protein strongly enhanced their ability to bind C3bi-coated E (EC3bi), a ligand for CD11b/CD18. LPS-binding protein is known to enable responses of cells to LPS by facilitating binding of LPS to CD14. Consistent with this, we found that preformed complexes of LPS with soluble rCD14 stimulated binding of ligand by CD11b/CD18 in a concentration-dependent manner. Known agonists that stimulate CD11b/CD18 binding activity on PMN all cause simultaneous enhancement of Fc-mediated phagocytosis. However, LPS presented in complex with either serum proteins or CD14 failed to stimulate the ingestion of ElgG by PMN. The number of FcRs and their ability to bind ligand were not affected by treatment with LPS, nor were they compromised in their ability to respond to other agonists. These results suggest that LPS generates intracellular signals that alter the ability of CD11b/CD18 to bind ligand, but this alteration is not sufficient to promote phagocytosis of IgG-coated particle. This conclusion was confirmed by showing that PMN treated with LPS and serum produced a lipid with the properties of integrin-modulating factor 1: acetone extracts of these cells stimulated CD11b/CD18 adhesive capacity on PMN. However, the lipid did not enhance Fc-mediated phagocytosis. These studies suggest that CD14 affects CD11b/CD18 function by inducing the synthesis of a lipid such as IMF-1, and that this lipid affects only the binding activity, not the phagocytosis-promoting capacity of CD11b/CD18.
Eosinophil transendothelial migration induced by cytokines. III. Effect of the chemokine RANTES.
Authors: Ebisawa M , Yamada T , Bickel C , Klunk D , Schleimer R P 
Published: December 2022

Abstract
Selective eosinophil recruitment occurs after experimental Ag challenge and in tissue sites of allergic diseases. The mechanisms of selective eosinophil migration are still unknown. In our study, we examined the ability of chemokines to induce transendothelial migration (TEM) of eosinophils in vitro. Among the chemokines tested, only RANTES induced eosinophil TEM. RANTES failed to induce TEM of neutrophils. Interestingly, IL-8 induced neutrophil TEM and had no effect on eosinophil TEM. RANTES-induced TEM was concentration-dependent and was inhibited by Abs directed against the beta 2 integrin CD18. When IL-1-activated endothelial cells were utilized, RANTES-induced TEM also involved the eosinophil beta 1 integrin VLA-4. RANTES did not increase eosinophil adhesion to either resting or IL-1-activated endothelial cells, nor did the chemokine increase CD11b or decrease L-selectin expression. A gradient of RANTES appears to be required for eosinophil TEM. Pre-exposure of eosinophils to IL-5 dramatically potentiated the TEM response to RANTES. These findings suggest that the chemokine RANTES is a potent and selective inducer of eosinophil TEM. Because RANTES appears to be produced in vivo during allergic reactions or in allergic diseases, we speculate that these findings may have some direct relevance to the mechanism of selective eosinophil recruitment in vivo in humans.
Tenidap modulates cytoplasmic pH and inhibits anion transport in vitro. II. Inhibition of IL-1 beta production from ATP-treated monocytes and macrophages.
Authors: Laliberte R , Perregaux D , Svensson L , Pazoles C J , Gabel C A 
Published: December 2022

Abstract
IL-1 beta is an important inflammatory mediator produced by monocytes and macrophages after LPS stimulation. In the absence of a secondary stimulus, however, little IL-1 beta is released into the medium. Previously, ATP was shown to promote the release and proteolytic maturation of IL-1 beta from LPS-stimulated murine peritoneal macrophages. Tenidap, a new anti-inflammatory and antiarthritic agent, inhibited the release and maturation of IL-1 beta induced in vitro by ATP treatment of murine peritoneal macrophages. Tenidap's inhibitory activity was mimicked by other agents that blocked anion transport, such as UK5099 and DIDS. In contrast, cyclooxygenase-inhibiting nonsteroidal anti-inflammatory drugs, such as piroxicam and naproxen, did not impair ATP-induced post-translational processing. Human monocytes responded to LPS to produce IL-1 beta, but externalized little of their newly synthesized cytokine. ATP at concentrations &gt; or = 2 mM promoted IL-1 beta release from these cells. The degree to which the released cytokine was proteolytically processed to its biologically active 17-kDa species, however, depended on the pH of the medium; a greater processing efficiency was observed at slightly acidic (pH 6.9) values. Tenidap and other anion transport inhibitors effectively prevented the ATP response of cultured human monocytes. Likewise, LPS-stimulated human alveolar macrophages responded to ATP by releasing 17-kDa IL-1 beta, and tenidap inhibited this response. The ATP-induced release and maturation of IL-1 beta from human monocytes and macrophages, therefore, was suppressed by anion transport inhibitors, suggesting that anion conductance is a necessary component of the ATP-promoted externalization mechanism. In view of IL-1's importance as an inflammatory mediator, tenidap may demonstrate novel anti-inflammatory activities by virtue of its inhibition of the post-translational release and maturation of this cytokine.
Transforming growth factor-beta prevents stem cell factor-mediated rescue of mast cells from apoptosis after IL-3 deprivation.
Authors: Mekori Y A , Metcalfe D D 
Published: December 2022

Abstract
IL-3-dependent mast cells undergo apoptosis upon removal of IL-3, an event that is prevented by the addition of stem cell factor (SCF) acting through its receptor c-kit, suggesting that SCF provides a mechanism to allow mast cells to survive and to differentiate in tissues in the relative absence of IL-3. This observation is consistent with the thesis that the microenvironment, in part, controls mast cell number and viability by modulating SCF production and release. The purpose of the present study was to determine whether a second factor, TGF-beta 1, was capable of modifying the SCF-mediated survival pathway. TGF-beta 1 (1 and 10 ng/ml), known to be an important regulator of cell growth and function, did inhibit the SCF-mediated rescue from apoptosis in IL-3-deprived mast cells. TGF-beta 1 exerted its inhibitory effect on SCF-mediated rescue from apoptosis, even when added 4 h after the addition of SCF. In contrast, TGF-beta 1 had no substantial effect on the viability of mast cells that were grown in the presence of IL-3. TGF-beta 1 also had no noticeable effect on viability and proliferation of a growth factor-independent mast cell line. The inhibitory effect of TGF-beta 1 was neutralized by specific anti-TGF-beta mAb. TGF-beta 1 did not affect the expression of c-kit, as determined by using flow cytometric analysis of mast cells labeled with FITC-conjugated anti-c-kit. These results demonstrate how SCF and TGF-beta may act in concert to regulate mast cell numbers under physiologic or pathologic conditions.
Effective graft-versus-leukemia effects independent of graft-versus-host disease after T cell-depleted allogeneic bone marrow transplantation in a murine model of B cell leukemia/lymphoma. Role of cell therapy and recombinant IL-2.
Authors: Weiss L , Lubin I , Factorowich I , Lapidot Z , Reich S , Reisner Y , Slavin S 
Published: December 2022

Abstract
After allogeneic bone marrow transplantation (BMT) for leukemia, beneficial graft-vs-leukemia (GVL) effects are usually accompanied by potentially serious graft-vs-host disease (GVHD). Because T cell depletion is the only effective way to prevent GVHD it seems important to understand whether effective GVL can develop after BMT with T cell depletion in GVHD-free recipients. Well-established C57BL/6--&gt;BALB/c chimeras that were free of GVHD, reconstituted with T cell-depleted allogeneic bone marrow cells, and inoculated 3 mo after BMT with a high inoculation of murine B cell leukemia (BCL1) showed no evidence of disease, whereas all control mice developed leukemia and died within 58 days. Results from adoptive transfer experiments in secondary naive BALB/c recipients indicated that all BCL1 cells were eliminated in the chimeras within 14 days. Hence, complete resistance to BCL1 developed in the chimeras despite complete tolerance to host alloantigens. The GVL effects observed in tolerant chimeras were further amplified by administration of immunocompetent allogeneic C57BL/6 spleen cells, low dose rIL-2, or both for 5 days. Our data suggest that GVL effects can develop even after T cell depletion in the absence of clinically overt GVHD and that GVL can be further amplified by rIL-2, either with or without use of additional immunocompetent donor T cells. Our data may provide the basis for new approaches to induce effective GVL after allogeneic BMT with cell therapy and rIL-2 at the stage of minimal residual disease, while avoiding early GVHD induced by the BMT procedure.
IL-1 beta-converting enzyme is present in monocytic cells as an inactive 45-kDa precursor.
Authors: Ayala J M , Yamin T T , Egger L A , Chin J , Kostura M J , Miller D K 
Published: December 2022

Abstract
The major form of IL-1 beta-converting enzyme (ICE) identified in THP.1 monocytic cells and human monocytes is the 45-kDa precursor protein (p45), which is found in the cytoplasm. Cytoplasmic extracts of these cells show no pIL-1 beta cleavage activity, indicating that the p45 has no detectable catalytic activity. pIL-1 beta cleavage activity can only be observed after incubation in vitro when p45 breaks down to the active p20 form of the enzyme. LPS stimulation of human monocytes or THP.1 monocytic cells results in no change in the amount of p45 or its activity and no detectable appearance of p20 ICE. Immunoprecipitation of [35S]Met-labeled LPS-stimulated monocyte extracts revealed only p45 with no other co-precipitating protein. The inability to identify active ICE in stimulated monocytic cells was probably a reflection of the very low levels of active ICE present.
Acquisition of iron bound to low molecular weight chelates by human monocyte-derived macrophages.
Authors: Olakanmi O , Stokes J B , Britigan B E 
Published: December 2022

Abstract
The iron content of tissue macrophages increases under conditions of elevated extracellular iron. Studies of macrophage iron acquisition have generally focused on iron uptake from transferrin via receptor-mediated endocytosis. However, in vivo macrophages are also exposed to extracellular low m.w. iron chelates, particularly under conditions of iron overload. Therefore, we examined the mechanism of iron acquisition from low m.w. chelates by human monocyte-derived macrophages. Iron acquisition was influenced by the nature of the iron chelate: Fe-ascorbate &gt; Fe-citrate &gt; Fe-nitrilotriacetate (NTA) = Fe-ADP &gt; Fe-glycyl-L-histidyl-L-lysine &gt; Fe-diethylenetriamine pentaacetic acid &gt; Fe-EDTA = Fe-deferoxamine. With the exception of Fe-EDTA and Fe-deferoxamine, iron acquisition was greater than that with diferric transferrin. As assessed by using iron acquisition from NTA as a model, the process is temperature dependent, but pH independent (pH 5 to 8), and is influenced by the medium in which the cells are suspended. Acquisition is not affected by NaF, 2-deoxy-D-glucose, NaCN, or monocyte-derived macrophage exposure to trypsin, pronase, phenylarsine oxide, dihydrocytochalasin B, filipin, nystatin, or digitonin. The rate of iron acquisition from NTA is induced by iron pre-exposure as well as aluminum. In contrast, NTA chelates of other transition metals (Cd, Cu, Ga, Mn, and Zn) inhibited iron uptake by 20 to 80%. Unlike results obtained with Ga-NTA, Ga(NO3)3 increased iron uptake from NTA. Data obtained with neutrophils, and undifferentiated U937 and HL-60 cells were similar, which suggests that myeloid cells share this pathway for iron acquisition. Iron acquisition via this mechanism may allow macrophages and other leukocytes to clear local states of iron overload in vivo.
Severe combined immunodeficient mice engrafted with human splenocytes have functional human T cells and reject human allografts.
Authors: Alegre M L , Peterson L J , Jeyarajah D R , Weiser M , Bluestone J A , Thistlethwaite J R 
Published: December 2022

Abstract
Previous studies have shown that human hemopoietic cells can be adoptively transferred into immunodeficient C.B-17 scid/scid (SCID) mice that lack autologous T and B lymphocytes, to generate chimeric animals. The future development of novel immunomodulatory drugs in transplantation will depend increasingly on experimental animal models to investigate the properties of the agents on human cells before starting clinical trials. However, in previous models of SCID mice engrafted with human PBLs, human T cells have been found either to be in an unresponsive state, unable to respond to mitogenic stimulations in vitro, or to mediate skin graft rejection only when HLA-primed in vivo before their adoptive transfer into SCID mice. In addition, T cells and other leukocyte subsets engraft quite poorly in the lymphoid tissues of the animals. In an attempt to develop a useful model for transplantation research, we have inoculated SCID mice with fresh human splenocytes from cadaveric organ donors (hu-Spl-SCID mice). In this model, various leukocyte subsets engraft effectively in different lymphoid compartments. In addition, human T cells retain their proliferative responses to mitogens and to alloantigens when tested 3 wk after engraftment into SCID mice. Finally, mice engrafted with unprimed human spleen cells acutely reject human foreskin allografts. Treatment of hu-Spl-SCID mice with OKT3, an immunosuppressive mAb directed against the human CD3 complex associated with the TCR, prevents the rejection of most human skin allografts, indicating a major role for human T cells in this phenomenon. Thus, this hu-Spl-SCID model may be useful for the study of immunosuppressive therapies in a preclinical in vivo setting.
Thymic stroma exposed to arylhydrocarbon receptor-binding xenobiotics fails to support proliferation of early thymocytes but induces differentiation.
Authors: Kremer J , Gleichmann E , Esser C 
Published: December 2022

Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 3,3',4,4'-tetrachlorobiphenyl (TCB), two ubiquitous environmental pollutants, accelerate thymocyte maturation, and eventually lead to thymus atrophy. These processes are mediated by binding of TCDD or TCB to the cytosolic arylhydrocarbon receptor (AhR) abundant in the thymus, which acts as a ligand-activated transcription factor. At several stages of their maturation thymocytes need the interaction with thymus stroma. We tested whether thymocytes themselves or the thymus stroma are targets of AhR-binding compounds for interference with thymocyte maturation. We depleted fetal thymus lobes from proliferating cells, i.e., thymocytes, by treatment with deoxyguanosine and recultivated them with immature thymocytes (CD4-CD8-), exposing either the stroma or the thymocytes to TCDD or TCB before recultivation. Although CD4-CD8- immature thymocytes could differentiate in TCB-treated stroma, expansion of the cells was severely impaired. Selective exposure of thymocytes to AhR-binding compounds likewise did not impair the capacity of differentiation of CD4-CD8- thymocytes. These cells, however, could expand when transferred into new lobes that had not been exposed to TCDD or TCB. TCB treatment of fetal thymi leads to an accumulation of phenotypically mature CD4-CD8+ cells. We show here that these cells do not belong to the transient CD4-CD8+ thymocytes, as previously suggested, because in recultivation experiments they do not give rise to any thymocyte subset further down the maturation pathway.
Establishment and characterization of nurse cell-like clones from human skin. Nurse cell-like clones can stimulate autologous mixed lymphocyte reaction.
Authors: Iwagami S , Furue S , Toyosaki T , Horikawa T , Doi H , Satomi S , Itoh T , Sakata T , Suzuki R 
Published: December 2022

Abstract
We have established nurse cell-like clones from long-term cultures of the human skin. These human skin nurse cell (HSNC)-like clones were type I collagen+, type IV collagen-, vimentin+, cytokeratin-, CD44+, CD54+, and weakly positive for VCAM-1, and easily identified by the pseudoemperipolesis that allowed T lymphocytes to migrate beneath the HSNCs. HSNCs and various T cell lines formed a typical complex in the hanging drop culture system. The majority of human and murine T cells, and some of the tumor cell lines other than T cells, including B lymphoma and myeloblastoma cells, migrated beneath the HSNC clones. HSNC clones produced various cytokines, including IL-6, IL-7, IL-8, IL-9, granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (CSF-1), TGF-beta 1, and c-kit ligand, but could not produce IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, TNF-alpha, or TNF-beta. These characteristics were similar to those of nurse cells established from the murine thymus. Furthermore, IFN-gamma-pretreated HSNC clones that expressed MHC class II Ags induced autologous mixed lymphocyte reaction (AMLR) in autologous PBMCs to proliferate and exhibit the cytotoxicity against altered autologous cells and various tumor cells. These results suggest that HSNCs play an important role in the immunoregulation at skin tissues.
Staphylococcal protein A induces biased production of Ig by VH3-expressing B lymphocytes.
Authors: Kristiansen S V , Pascual V , Lipsky P E 
Published: December 2022

Abstract
Staphylococcal protein A (SPA) is known to bind preferentially to the VH3 family of Ig heavy chain variable gene products. The current studies were conducted to examine the functional capacity of SPA to induce Ig production by VH3-expressing human B cells preferentially. Human peripheral blood B cells stimulated with anti-CD3-activated T cells or the Wood 46 strain of Staphylococcus aureus, which lacks SPA, expressed IgM containing all VH families, as detected by reverse transcription-PCR. In contrast, stimulation with SPA containing S. aureus or SPA-Sepharose resulted in biased expression of VH3 containing IgM. Similarly, cord blood B cells that require costimulation for Ig production induced by anti-CD3-activated T cells produced only VH3 containing IgM on costimulation with SPA containing S. aureus. The sequences of 21 VH3 IgM gene products derived from different B cell sources were determined and found to include at least nine members of the VH3 family, which were both in germ-line configuration and somatically mutated. Use of DH and JH was diverse. Analysis of these VH3 gene products revealed conserved residues in FR1 and 3'CDR2/FR3, which are candidates to play a role in SPA-mediated activation of VH3-expressing B cells. Like T cell superantigens, SPA probably interacts with residues in the partially solvent exposed regions of the heavy chain molecule outside the classical Ag binding site and provides a signal that can lead to Ig production by human B cells expressing VH3.
Studies with MHC-deficient knock-out mice reveal impact of both MHC I- and MHC II-dependent T cell responses on Listeria monocytogenes infection.
Authors: Ladel C H , Flesch I E , Arnoldi J , Kaufmann S H 
Published: December 2022

Abstract
Mutant mice with a defined genetic defect in the beta 2-microglobulin (beta 2m) or the H2-I-A beta chain, which are virtually devoid of functional CD8 or CD4 alpha beta T cells, respectively, were employed for analyzing immune mechanisms involved in acquired resistance against Listeria monocytogenes. Although the lethal dose of L. monocytogenes was markedly lower for either mouse mutant as compared with their heterozygous control littermates, both beta m -/- and A beta -/- mutants were able to resolve low dose infection. However, in both mouse mutants, the course of disease was exacerbated and clearance was markedly delayed. Vaccine induced immunity against a secondary high dose infection lethal for naive animals was also impaired in beta 2m -/- and A beta -/- mice. However, both mutant mice were still capable of controlling secondary infection. Based on numbers of L. monocytogenes organisms in spleens, beta 2m -/- mutants suffered more dramatically from primary and secondary infection than A beta -/- mice. Ag-induced IFN-gamma secretion was impaired during the early phase of infection in beta 2m -/- mice and at later stages in A beta -/- mice. Modulation of gamma delta T cells by mAb treatment led to significant increase in bacterial load of spleens in both beta 2m -/- and A beta -/- mice. Finally, the development of granulomatous lesions was markedly affected in both mutants. In beta 2m -/- mutants, infiltrative lesions appeared and in A beta -/- mice few inflammatory islets with necrotic centers developed. These data demonstrate the importance of both MHC I- and MHC II-dependent immune mechanisms in acquired resistance to L. monocytogenes and point to the necessity of a coordinated interaction between CD8 and CD4 alpha beta T cells (and probably gamma delta T cells) in anti-L. monocytogenes resistance.