bluuebunny/crossref_metadata_2025_split huggingface dataset:
Second signal activity of IL-12 on the proliferation and IL-2R expression of T helper cell-1 clone.
Authors: Yanagida T , Kato T , Igarashi O , Inoue T , Nariuchi H 
Published: December 2022

Abstract
In these experiments, effects of IL-12 on the proliferation and IL-2R expression of Th1 and Th2 clones were studied. Although neither Th1 nor Th2 clones proliferated on an Ag stimulation with B cell APC, Th1 clones but not Th2 clones, exhibited IL-2-dependent proliferation in the presence of IL-12 in response to the Ag stimulation. The IL-2R alpha-chain was also shown to be induced on Th1 clones when they were stimulated with B cell APC in the presence of IL-12. Effects of IL-12 on these T cell functions were indicated to be exerted in concert with IL-2, although IL-12 did not enhance IL-2 production of Th1 clones. Cytokines produced by Th1 clones such as IFN-gamma and TNF-alpha were indicated not to be involved in induction of the IL-2R alpha-chain expression or proliferation. IL-12 also induced proliferation and IL-2R alpha-chain expression of Th1 clone stimulated with anti-CD3 in the absence of APC, indicating that IL-12 exerted the effect on Th1 cells directly and other costimulator signal from APC is not required for the function of IL-12. In contrast to IL-12, IL-1 induced proliferation and IL-2R alpha-chain expression of Th2 clones stimulated with Ag on B cell APC. The failure of IL-12 in the induction of IL-2R alpha-chain expression on Th2 clone seemed not to be caused by the IL-4 produced by the clone. These results suggest that IL-12 plays an important role in IL-2R alpha-chain expression and proliferation of Th1 clones, but not Th2 clones, as a second signal.
MHC class I and non-MHC-linked capacity for generating an anti-viral CTL response determines susceptibility to CTL exhaustion and establishment of virus persistence in mice.
Authors: Moskophidis D , Lechner F , Hengartner H , Zinkernagel R M 
Published: December 2022

Abstract
The influence of the murine MHC gene complex H-2 class I alleles or of the genetic background and the role of virus variants on establishment of a persistent infection with lymphocytic choriomeningitis virus (LCMV) was analyzed in immunocompetent mice of H-2d haplotype by evaluation of cytotoxic T cell responses. Susceptibility to establishment of a virus carrier state increased in various H-2d mice with lower CTL response and slower CTL kinetics. Low responder BALB/c-H-2dm2, lacking H-2Ld molecules to present the major T cell epitope amino acids 118-126 of the LCMV nucleoprotein or DBA/2 mice possessing relatively few CD8+ T cells, were more susceptible than high responder BALB/c mice expressing H-2Ld. Additional critical factors were LCMV isolate and dose of infection. The rapidly replicating LCMV-DOCILE and Cl 13 Armstrong induced viral persistence readily, whereas the slowly replicating parental virus strains WE or Armstrong did not. The presented findings illustrate a model of MHC-linked or MHC-unlinked susceptibility for virus persistence and may help to explain pathogeneses of chronic virus infections in humans that are often associated with slowly progressing immunopathology.
Regulation of leukemia inhibitory factor synthesis in cultured human astrocytes.
Authors: Aloisi F , Rosa S , Testa U , Bonsi P , Russo G , Peschle C , Levi G 
Published: December 2022

Abstract
We have examined the ability of human astrocytes to synthesize and secrete leukemia inhibitory factor (LIF), which is a multifunctional cytokine that controls cell proliferation and differentiation in many tissues, including the nervous system. Astrocyte-enriched cultures, prepared from 8- to 9-wk-old embryonic brains, expressed LIF mRNA and secreted LIF protein. LIF synthesis was significantly increased by the cytokines IL-1 beta, TNF-alpha, and TGF-beta 1, but not by IFN-gamma, IL-6, or LPS. No major differences in basal and cytokine-inducible LIF production were detected among astrocyte populations obtained from different brain areas. LIF synthesis was lower in serum-free than in serum-containing astrocyte cultures. A role for protein kinase C in the regulation of astrocyte LIF production was suggested by the findings that phorbol esters induced both LIF mRNA and protein and that the cytokine-induced LIF increase was partially antagonized by relatively selective inhibitors of protein kinase C such as H7 and staurosporine. Human leptomeningeal fibroblasts also expressed LIF gene and protein. Astrocytes produced LIF and responded to cytokines with increased LIF synthesis only after being subcultured, and not when grown in primary cultures in close contact with neurons. Our findings suggest that in vivo induction of astrocyte LIF secretion might occur in pathologic conditions as a consequence of both alterations of neuronal-glial interactions and a local increase in the level of inflammatory cytokines.
IL-1 beta amplifies bradykinin-induced prostaglandin E2 production via a phospholipase D-linked mechanism.
Authors: Angel J , Audubert F , Bismuth G , Fournier C 
Published: December 2022

Abstract
The proinflammatory cytokine IL-1 was shown to increase the responsiveness of synovial cells to the potent inflammatory peptide bradykinin (BK). We have investigated the biochemical events linked to this amplifying action of IL-1. Stimulation of synoviocytes with only BK elicited a rapid increase in inositol phosphates and a concomitant accumulation of diacylglycerol (DAG), monoacylglycerol, and free arachidonic acid (AA). In contrast, IL-1 did not stimulate any of these events. Thus, BK can induce AA release via the hydrolysis of phosphatidylinositols by a phospholipase C (PLC). BK also activated a phospholipase D (PLD) to cleave phosphatidylcholine (PC), because it caused an increase in phosphatidic acid (PA) content and a sustained DAG formation, which both were inhibited by ethanol in [3H]myristic acid-labeled cells. Moreover, the addition of ethanol diverted PLD into the formation of phosphatidylethanol (PEt) thus inhibiting the amounts of PA and DAG formed. Priming of synovial cells with rIL-1 beta 24 h before exposure to BK in the presence of ethanol further enhanced the BK-induced formation of PEt. Conversely, preincubation with IL-1 did not influence the BK-induced PLC activation nor did it alter the liberation of AA. Finally, we demonstrated that the IL-1-mediated amplification of PGE2 release in response to BK was reduced by the presence of ethanol in the culture medium, suggesting that part of the synergistic action of IL-1 and BK on prostanoid production was dependent on the activation of the PC-specific PLD pathway.
Recombinant IL-1 receptor antagonist protects against TNF-induced lethality in mice.
Authors: Everaerdt B , Brouckaert P , Fiers W 
Published: December 2022

Abstract
The possible role of induced IL-1 in a number of in vivo actions of TNF was investigated. We were particularly interested to know whether a species-specific induction of IL-1 might explain the important differences observed between murine TNF and human TNF in systems such as lethal shock and the induction of long lasting, high levels of circulating IL-6 in mice. We also studied the possible involvement of IL-1 in the sensitization to TNF observed in tumor-bearing mice or in combination with D(+)-galactosamine or RU38486, particularly because such sensitization results in the loss of species-specific differences between both TNF. Using a specific rIL-1R antagonist (IL-1ra), which inhibits the binding of IL-1 to the IL-1R type I, we were able to protect mice against a lethal murine TNF injection. However, the induction of high levels of circulating IL-6 by murine TNF was not affected, although IL-1ra almost completely blocked the induction of IL-6 by exogenously administered IL-1. Furthermore, the increased susceptibility of tumor-bearing mice to human TNF, relative to control mice, or the sensitization by co-administration of RU38486 or D(+)-galactosamine do not seem to be mediated by IL-1.
HIV-1 Nef activity in murine T cells. CD4 modulation and positive enhancement.
Authors: Rhee S S , Marsh J W 
Published: December 2022

Abstract
Immediately after infection of the targeted cell by HIV-1, proviral gene expression is limited to the three regulatory proteins, Tat, Rev, and Nef, with the nef transcript representing nearly 80% of total expression. Additionally, simian immunodeficiency virus Nef has been shown to be essential for high in vivo titer and the development of immunodeficiency. Recent findings demonstrate that the negative effects of Nef expression, as first defined in transformed T cell lines, are not present when Nef is expressed in primary human T cells or in T cells from transgenic mice, in which one sees moderate positive enhancements of HIV replication and the T cell activation process, respectively. We find that Nef expression in an Ag-specific murine T cell hybridoma results in both the down-modulation of CD4, as seen in primary cells and human T cell lines, and a positive enhancement of the TCR response to stimuli. Examination of a CD4- cell demonstrated that the positive enhancement is independent of CD4 expression or modulation. CD4 down-modulation is shown to be caused by a post-Golgi, acid-dependent process, which dramatically decreases the lifespan of the CD4 molecule. The TCR, Thy Ag, and CD45 remained unchanged in their surface expression. These findings suggest that Nef alters the normal routing and residencies of the CD4 molecule and that the positive effect of Nef on T cell activation is independent of this modulation.
An H2-T MHC class Ib molecule presents Listeria monocytogenes-derived antigen to immune CD8+ cytotoxic T cells.
Authors: Bouwer H G , Lindahl K F , Baldridge J R , Wagner C R , Barry R A , Hinrichs D J 
Published: December 2022

Abstract
Mouse spleen T cells can adoptively transfer immunity to Listeria monocytogenes; this activity was markedly enhanced by stimulation with Con A in vitro before transfer. The enhanced and prolonged protection against L. monocytogenes in vivo was correlated with enhanced lysis in vitro of target cells infected with strains of L. monocytogenes that produce listeriolysin O (LLO). One of the targets of such cytotoxic cells from BALB/c (H2d) mice was a peptide that corresponded to amino acids 91 to 99 (p91-99) of the LLO molecule, which satisfies the binding motif of H2-Kd. Listeria-immune CD3+CD8+, but not CD3+CD8-, cells could also lyse H-2-incompatible, infected target cells. Immune cells from C57BL/6 (H2b) mice lysed allogeneic H-2d target cells infected with L. monocytogenes or a Bacillus subtilis transformant that secretes LLO, but did not lyse targets pulsed with p91-99. This H2-unrestricted cytolysis was therefore directed at a fragment of the LLO molecule other than p91-99. Listeria-infected bone marrow macrophages from congenic and recombinant strains of mice were lysed only when they shared the H2-T region or were Qa1-compatible with the immune cytotoxic cells; sharing of the H2-D, Q, or M region was insufficient. Thus, the immune response to L. monocytogenes included cytolytic CD8+ cells that recognized endogenously processed Listeria-derived Ags in the context of the class Ia H2-K molecule, as well as a class Ib H2-T molecule.
Efficient tumor cell lysis mediated by a bispecific single chain antibody expressed in Escherichia coli.
Authors: Gruber M , Schodin B A , Wilson E R , Kranz D M 
Published: December 2022

Abstract
Recent advances in the expression of Abs in Escherichia coli have raised the possibility that virtually any specificity can be obtained by either cloning Ab genes from characterized hybridomas or by de novo selection using Ab gene libraries. Bispecific Abs have been more difficult to engineer because of problems inherent in the proper folding and association of VH and VL domains. In this report, a model system for expressing and testing the activity of a single chain bispecific Ab was used. The Ab contained the VH and VL genes from the anti-TCR Ab 1B2 joined by a 25 amino acid residue linker to the VH and VL genes from the anti-fluorescein Ab 4420. The 57-kDa single chain bispecific Ab (scFv2) was purified in a single step by affinity chromatography through a fluorescein column at a yield of 1 mg/L of bacterial culture. Despite the presence of 1B2 V regions at the NH2-terminus and a 10-residue c-myc peptide at the COOH-terminus, the refolded protein had an affinity for fluorescein that was nearly identical with the monospecific single chain Ab. The scFv2 also bound the TCR of the mouse CTL clone 2C and redirected the lysis of human tumor cells that had fluorescein covalently linked to their surface. Lysis was mediated at scFv2 concentrations that were 100-fold lower than the concentrations of Ab that inhibited normal recognition by CTL 2C. These results show that single chain bispecific Abs can mediate CTL lysis of target cells without the immunosuppressive side effects associated with the use of anti-TCR Abs.
Regulation of neutrophil responses by phosphotyrosine phosphatase.
Authors: Cui Y , Harvey K , Akard L , Jansen J , Hughes C , Siddiqui R A , English D 
Published: December 2022

Abstract
By using immunofluorescent flow cytometry, we observed a profound up-regulation of CD45 on the plasma membrane of neutrophils exposed to low levels of a culture supernatant of the Gram-negative pathogen, Fusobacterium nucleatum (FN). Plasma membranes of neutrophils freshly prepared form human blood possessed little enzymatically active phosphotyrosine phosphatase. The activity of this enzyme was markedly potentiated in plasma membranes prepared from cells preexposed to the FN culture supernatant. This activity was vanadate sensitive and could be immunoprecipitated with anti-CD45 Ab. Cells preexposed to the FN culture supernatant were inhibited in their ability to release superoxide when challenged with the bacterial chemotactic factor, FMLP, but not PMA. The tyrosine kinase inhibitor, genistein, likewise inhibited FMLP but not PMA-induced superoxide release. Pretreatment of neutrophils with vanadate reversed FN-mediated inhibition of FMLP-triggered superoxide release but had no effect on genistein-mediated inhibition of FMLP-induced superoxide release. Of several proteins tyrosine phosphorylated in response to treatment of neutrophils with FMLP, Western analysis revealed one (m.w. approximately 93,000) that was lost when FMLP-stimulated cells were exposed to FN. This effect was inhibited when the cells were preexposed to vanadate. These results are consistent with the hypothesis that plasma membrane tyrosine phosphatase modulates FMLP-induced superoxide release by reversing the effects of tyrosine kinases activated in the initial phases of cell stimulation.
Transfection of thyroid autoantigens into EBV-transformed B cell lines. Recognition by Graves' disease thyroid T cells.
Authors: Mullins R J , Chernajovsky Y , Dayan C , Londei M , Feldmann M 
Published: December 2022

Abstract
Autologous EBV-transformed B cell lines (EBVL) from a patient with Graves' disease (GD) were transfected with the expression vector pREP4 encoding thyroid peroxidase (TPO), the thyroid-stimulating hormone receptor (TSHR), or chloramphenicol acetyl transferase. The relevant proteins were expressed. The capacity of EBVL to present transfected Ag was assessed by using EBVL transfected with TPO (EBVL-TPO) to stimulate TPO-specific T cells cloned from autologous thyroid tissue; stimulation indices greater than 100 were consistently obtained, even at low APC:T cell ratios. EBVL-TPO and EBVL transfected with TSHR (EBVL-TSHR) were used to characterize the Ag specificity of five thyroid epithelial cell-specific T cell clones. Despite previous unresponsiveness to recombinant TPO or purified thyroglobulin, four of these clones responded vigorously to EBVL-TPO but none responded to EBVL-TSHR. Experiments were then performed to determine whether transfected EBVL were presenting endogenously synthesized TPO, or were taking up and reprocessing exogenous Ag shed from the surface of adjacent cells. The stimulatory capacity of EBVL-TPO was not transferable to untransfected EBVL by cell-free culture supernatant and to only a minor degree by EBVL-TPO-derived cell membrane fragments, indicating that the majority of the TPO presented by the transfected EBVL is endogenously synthesized. The clear and reproducible proliferative responses obtained illustrate the usefulness and potency of this method of Ag presentation to T cells. Because this system obviates the need for large numbers of autologous APC or purified recombinant Ag, it will be useful for obtaining autoantigen-reactive T cells and to help define the autoantigenic epitopes recognized.
Antigen presentation by human dermal microvascular endothelial cells. Immunoregulatory effect of IFN-gamma and IL-10.
Authors: Vora M , Yssel H , de Vries J E , Karasek M A 
Published: December 2022

Abstract
Human dermal microvascular endothelial cells (HDMEC) play a central role in many aspects of the inflammatory and immune reactions in skin. HDMEC display a phenotypic diversity ranging from cells with an epithelioid morphology to those that show both morphologic and biochemical characteristics of macrophages. Here it is shown that HDMEC possess the capability to both process and present Ags. T lymphocyte clones specific for peptide p94-104, which are derived from the protein of group I allergen of Dermatophagoides pteronyssinus, a major house dust mite allergen, and restricted by HLADR11, proliferated specifically to stimulation with the group I allergen of D. pteronyssinus and with peptide p94-104 presented by HDMEC. Preincubation for 48 h with IFN-gamma enhanced the expression of class II MHC Ags on HDMEC, which in turn increased the capacity of HDMEC to present Ag. When HDMEC were primed with Ag in the presence of IL-10, a 75% inhibition of Ag-specific T cell proliferation was observed. IL-10 also inhibited T cell proliferation induced by IFN-gamma-stimulated HDMEC. These findings demonstrate that HDMEC possess the ability to process and present Ag to CD4+ T cells and that these reactions are stimulated by IFN-gamma and inhibited by IL-10. The reduced Ag-presenting capacity of HDMEC mediated by IL-10 is not associated with a down-regulation of class II MHC expression. No significant reduction of HLA-DR expression was detected either at the protein or gene level when HDMEC were incubated with IFN-gamma and IL-10 as compared with incubation with IFN-gamma alone. The profound down-regulatory effect of IL-10 on Ag presentation may provide a new pharmacologic approach to control inflammatory responses in skin.
Molecular cloning and characterization of a murine LPS-inducible cDNA.
Authors: Lee C G , Demarquoy J , Jackson M J , O'Brien W E 
Published: December 2022

Abstract
Murine macrophages respond to endotoxins by inducing a vast array of genes that play a major role in the host's response to infection and tumor growth. We have isolated and characterized a 1.8-kb cDNA, designated IRG2, from a cDNA library prepared from RNA isolated from the murine cell line, RAW 264.7, after bacterial LPS stimulation. The cDNA encodes a protein of 47 kDa that is the murine homologue of a small family of proteins described from IFN-induced human cells. The IRG2 message does not appear until 3 h after LPS exposure and its induction is dependent on new protein synthesis. IRG2 induction by LPS is slightly inhibited by the anti-inflammatory steroid, dexamethasone. Increasing cytosolic cAMP with either forskolin, dibutyryl cAMP, or 8-(4-chlorophenylthio)-cAMP caused marked inhibition of the LPS induction of IRG2. In contrast, activation of PKC with phorbol ester potentiated the LPS response. Removing extracellular Ca2+ with EGTA inhibited IRG2 induction; increasing intracellular calcium with the calcium ionophore A23187 led to enhanced levels of the IRG2 transcript. These data suggest that the induction of IRG2 occurs via a PKC pathway.
Modulation of Fc gamma and complement receptor function by the glycosyl-phosphatidylinositol-anchored form of Fc gamma RIII.
Authors: Edberg J C , Kimberly R P 
Published: December 2022

Abstract
Human neutrophils express two structurally distinct receptors for IgG, the transmembrane Fc gamma RII (CD32) and the glycosyl-phosphatidylinositol-linked Fc gamma RIII (CD16). To explore the respective functional roles of Fc gamma RII and Fc gamma RIII, we have used anti-receptor mAb fragments coupled with erythrocytes to quantify both individual and cooperative receptor functions. With individual receptor engagement, Fc gamma RII (E-IV.3) was much more efficient than Fc gamma RIIIB (E-3G8) in initiating phagocytosis (p &lt; 0.001). However, when identical total numbers of receptors were engaged, co-ligation of Fc gamma RII and Fc gamma RIIIB resulted in a phagocytic response, which was: 1) greater than that for either receptor alone (&gt; twofold Fc gamma RII alone (p &lt; 0.001) and &gt; 20-fold Fc gamma RIIIB alone (p &lt; 0.001)); 2) greater than the sum of Fc gamma RII and Fc gamma RIIIB (p &lt; 0.001); and 3) comparable to the phagocytic potential of Fc gamma RII in FMLP pre-activated neutrophils. This synergistic capacity of Fc gamma RIIIB also enabled CR phagocytosis. Furthermore, the capacity for Fc gamma RIIIB to interact synergistically with Fc gamma RII was preserved in FMLP-preactivated neutrophils. The activation of Fc gamma RII by Fc gamma RIIIB was associated with tyrosine phosphorylation of the Fc gamma RII cytoplasmic domain, which is essential for Fc gamma RII function and which, by analogy to the Ig alpha-chain of the B cell Ag receptor complex, the zeta-chain of CD3, and the gamma-chain of some Fc epsilon Rs and Fc gamma Rs, may enhance the binding and activation of Src or Syk family tyrosine kinases. Thus, Fc gamma RIIIB can affect multiple receptor families and play a role in achieving maximal Fc gamma R capacity, even in stimulated neutrophils in inflammatory sites.
Protective effect of an adenosine kinase inhibitor in septic shock.
Authors: Firestein G S , Boyle D , Bullough D A , Gruber H E , Sajjadi F G , Montag A , Sambol B , Mullane K M 
Published: December 2022

Abstract
Adenosine exhibits potent anti-inflammatory activities but its therapeutic use is limited by cardiovascular side effects. Inhibitors of an enzyme involved in adenosine metabolism, adenosine kinase (EC 2.7.1.20), were evaluated for their ability to enhance endogenous adenosine production. One novel adenosine kinase inhibitor, GP-1-515, was studied in two models of septic shock to assess its protective effects. GP-1-515 significantly decreased mortality in mice that received a lethal i.v. injection of endotoxin. The beneficial effect was accompanied by decreased neutrophil accumulation in the lungs and was reversed by an adenosine receptor antagonist, implying that the effects were mediated by endogenous adenosine. Plasma levels of TNF-alpha, but not IL-1 alpha or IL-6, were lower in the GP-1-515-treated animals. In a second model of sepsis, GP-1-515 increased survival in bacterial peritonitis in rats. The mechanism of action in both models was likely multifactorial, including adenosine-mediated inhibition of neutrophil adhesion, cytokine production, and oxygen radical generation. Adenosine kinase inhibitors have potent anti-inflammatory effects in vitro and in vivo and represent a novel therapeutic approach to the treatment of inflammatory diseases.