bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nitric oxide and TNF-alpha production by murine peritoneal macrophages activated with a novel 20-kDa protein isolated from Bacillus thuringiensis var. thuringiensis parasporal bodies.
Authors: Gomez-Flores R , Rodriguez-Padilla C , Mehta R T , Galan-Wong L , Mendoza-Gamboa E , Tamez-Guerra R 
Published: December 2022

Abstract
The effects of a novel 20-kDa protein isolated from Bacillus thuringiensis var. thuringiensis (BTp20) parasporal bodies on macrophage activation were investigated and compared with the activity of LPS. Murine resident or IFN-gamma-primed peritoneal macrophages (50 U/ml of IFN-gamma for 16 h) were treated with 50 microg/ml of BTp20, alone or in combination with LPS (1 to 100 ng/ml). BTp20 was not toxic for macrophages as determined by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction assay, however, 16% reduction of viability was observed when macrophages were treated with a combination of IFN-gamma, BTp20, and LPS at 100 ng/ml. BTp20 was able to stimulate significant cellular adherence and spreading, and significant production of nitrite and TNF-alpha by resident macrophages after 1.5 h of treatment; nitrite release, however, was induced with only 10 min of macrophage exposure to BTp20. BTp20 activities were significantly potentiated by IFN-gamma pretreatment. It was also observed that nitrite release by IFN-gamma-primed macrophages activated with LPS (1-100 ng/ml) was 20 times lower than that induced by IFN-gamma + BTp20. BTp20 and LPS independently stimulated significant TNF-alpha production by IFN-gamma-primed macrophages, the effect of BTp20 + LPS (1 and 10 ng/ml) combination was additive. In summary, this study demonstrated that BTp20 activates macrophage functions in the absence of IFN-gamma or LPS, and that IFN-gamma enhances BTp20 activities.
Immunoregulatory idiotypes stimulate T helper 1 cytokine responses in experimental Schistosoma mansoni infections.
Authors: Montesano M A , Freeman G L , Secor W E , Colley D G 
Published: December 2022

Abstract
Inbred male CBA/J mice with chronic Schistosoma mansoni infections develop two distinct syndromes. Hypersplenomegaly syndrome (HSS) demonstrates pathologic similarities to the hepatosplenic form of chronic human schistosomiasis, and moderate splenomegaly syndrome (MSS) resembles the asymptomatic intestinal form. Immunoaffinity-purified Abs against S. mansoni soluble egg Ags (SEA) from infected patients' sera differ idiotypically according to the donor's clinical form of the disease. We now show that immunoaffinity-purified anti-SEA Abs (Id) from MSS or HSS mice parallel idiotypic preparations of the analogous human clinical form by their differential ability to stimulate the proliferation of anti-Id T cells. MSS Id preparations stimulate spleen cells from either MSS or HSS animals. In contrast, HSS Id does not stimulate spleen cells from either group. In an anti-SEA ELISA, MSS and HSS Id preparations contained comparable levels of IgM and IgG1. However, the MSS Id preparation had higher levels of SEA-specific IgG2a and IgG2b than did HSS Id. The Ig isotypes of these Id preparations suggested differences in cytokine expression patterns. Studies of the cytokine profiles of the spleen cells responding to anti-SEA Id preparations demonstrated that while Id preparations from acutely infected mice stimulate IL-4 and IL-10 production, Id preparations from chronic MSS mice stimulate IFN-gamma production. HSS Id did not stimulate the production of any of these cytokines. The possibility that distinct immunoregulatory environments may contribute to the development of MSS and HSS correlates with earlier hypotheses that hepatosplenic pathology results at least in part from a lack of development or expression of appropriate regulatory Ids.
Destruction of follicular dendritic cells during chronic visceral leishmaniasis.
Authors: Smelt S C , Engwerda C R , McCrossen M , Kaye P M 
Published: December 2022

Abstract
Follicular dendritic cells (FDCs) play a pivotal role in the germinal center (GC) response and in the development and regulation of B lymphocytes. Pathologic changes in GCs and a loss of FDCs have previously been noted in various viral infections, notably HIV-1. However, such changes have not been formally described in a chronic parasitic infection. In BALB/c mice infected with Leishmania donovani, parasites persist in the spleen for long periods, with associated splenomegaly. To examine the fate of FDC during the course of this chronic infection, we used 1) immunohistology, with FDC-specific mAbs; and 2) passive immunization with immune complexes, followed by light and electron microscopy. This study demonstrates that destruction of FDCs and a concomitant loss of GCs are associated with chronic visceral leishmaniasis. These pathologic effects are notable from 4 wk postinfection. At 8 wk postinfection and beyond, FDC are almost undetectable by both immunohistology and functional immune complex trapping. The loss of FDCs is associated with the infiltration of heavily parasitized macrophages into the GC, and reduction in parasite burden by chemotherapy is able to retard the process of FDC destruction. These data directly demonstrate for the first time the loss of FDCs during a chronic parasite infection and suggest a mechanism underlying the aberrant regulation of B cell function in murine visceral leishmaniasis.
TNF-alpha, unlike other pro- and anti-inflammatory cytokines, induces rapid release of the IL-1 type II decoy receptor in human myelomonocytic cells.
Authors: Orlando S , Matteucci C , Fadlon E J , Buurman W A , Bardella M T , Colotta F , Introna M , Mantovani A 
Published: December 2022

Abstract
The present study was designed to investigate the effect of a series of cytokines on the release of the type II IL-1 decoy receptor, which represents a unique pathway of negative regulation of the IL-1 system. After 20 min, IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IFN-gamma, granulocyte-CSF, macrophage-CSF, and TGF-beta had little or no effect on IL-1 binding by human polymorphonuclear cells. In contrast granulocyte-macrophage-CSF and, to a greater extent, TNF markedly reduced IL-1 binding. The action of TNF was rapid, reaching 50% of its maximum (80%) at 2 min, and plateauing at 20 min with decrease in receptor number and no significant change in affinity. Loss of surface receptor was associated to rapid release of a 45-kDa IL-1-binding molecule identified as the decoy RII. TNF-induced release of the decoy RII was independent of protein synthesis and reactive oxygen intermediates. Monocytes showed a similar response to TNF, except for the size of the released molecule (approximately 60 kDa). TNF induced rapid release of its own receptors. In contrast IL-1beta affected neither its own receptors nor the TNF-R. TNF and, more efficiently, PMA caused release of the decoy RII in fibroblasts transfected with the full-length decoy RII or with a cytoplasmatic deletion mutant. TNF-induced decoy RII release represents an unidirectional pathway of communication in the interplay between the IL-1 and TNF system.
Inhibitory activity of IL-1 receptor antagonist depends on the balance between binding capacity for IL-1 receptor type 1 and IL-1 receptor type II.
Authors: Ruggiero P , Bossù P , Macchia G , Del Grosso E , Sabbatini V , Bertini R , Colagrande A , Bizzarri C , Maurizi G , Di Cioccio V , D'Andrea G , Di Giulio A , Frigerio F , Grifantini R , Grandi G , Tagliabue A , Boraschi D 
Published: December 2022

Abstract
A series of mutants of human IL-1 receptor antagonist (IL-1ra) has been designed by comparison of IL-1ra and IL-1beta structures in order to increase receptor antagonist capacity. Upon in vitro and in vivo assay of IL-1 antagonism, the IL-1ra mutants DoB 0039 (N91--&gt;R), DoB 0040 (T109--&gt;A) and DoB 0041 (N91/T109--&gt;R/A) could inhibit IL-1beta effects more efficiently than wild-type IL-1ra, with DoB 0041 being the most active. Analysis of the receptor-binding capacity of the IL-1ra mutants showed that all three mutants could inhibit binding of IL-1alpha or IL-1beta to IL-1RI-bearing cells more efficiently than wild-type IL-1ra. Conversely, binding of IL-1beta to IL-1RII-bearing cells could be inhibited by DoB 0041 much less efficiently than by wild-type IL-1ra. It is known that the two types of IL-1 receptors (IL-1RI and IL-1RII) play different roles in the regulation of IL-1 activity, with IL-1RI being solely responsible for cell triggering upon IL-1 binding, whereas IL-1RII acts as a scavenger of IL-1 and can thus be considered as a natural IL-1 inhibitor. Thus, the enhanced inhibitory capacity of DoB 0041 as compared with wild-type IL-1ra is explained in terms of better binding to the activating receptor IL-1RI and poorer interaction with the inhibitory receptor IL-1RII.
Genetically engineered nontoxic vaccine adjuvant that combines B cell targeting with immunomodulation by cholera toxin A1 subunit.
Authors: Agren L C , Ekman L , Löwenadler B , Lycke N Y 
Published: December 2022

Abstract
Cholera toxin (CT) is an exceptionally potent adjuvant but, unfortunately, also very toxic. Here we present a powerful new approach to separate toxicity from adjuvanticity by constructing a fusion protein that combines the enzymatically active cholera toxin A1 subunit (CTA1) with targeting to B cells. The CTA1 was genetically linked at its C-terminal end to two Ig-binding domains, DD, of staphylococcal protein A and produced in Escherichia coli. The highly purified, monomeric CTA1-DD fusion protein, with a molecular mass of 37 kDa, was found to exhibit strong ADP-ribosyltransferase activity and bound, via the DD moiety, to both Fc and Fab fragments and to all IgG subclasses--IgE, IgA, and IgM. After i.v. injection of the fusion protein, FACS analysis revealed binding of CTA1-DD to splenic IgM+ B cells, but not CD3+ T cells, indicating cell-specific targeting in vivo. Strikingly, we found that the adjuvant ability of CTA1-DD to enhance systemic IgG as well as mucosal IgA responses to the unrelated Ags, OVA, or keyhole limpet hemocyanin, administered i.v or intranasally, was comparable to that of intact CT. In addition, the enhancing effect on specific IgG1, IgG2a, and IgG2b responses mimicked that of CT and suggested involvement of both Th1 and Th2 CD4+ T cell activity. The CTA1-DD, as well as CT, up-regulated expression of the CD80 and CD86 molecules on the targeted B cells, indicating that enhanced T cell costimulation may be responsible for the adjuvant effect. Contrary to CT, however, CTA1-DD was completely nontoxic. Thus, the CTA1-DD adjuvant should find general applicability in systemic and mucosal vaccines, and the strategy used may also be explored for other regimens requiring targeted immunomodulation.
Attenuation of proinflammatory response by recombinant human IL-10 in human endotoxemia: effect of timing of recombinant human IL-10 administration.
Authors: Pajkrt D , Camoglio L , Tiel-van Buul M C , de Bruin K , Cutler D L , Affrime M B , Rikken G , van der Poll T , ten Cate J W , van Deventer S J 
Published: December 2022

Abstract
To determine the effects of IL-10 on cytokine and granulocyte responses during endotoxemia, two groups of eight healthy male volunteers were challenged with endotoxin (4 ng/kg) on two occasions, once in combination with placebo injection, and once in conjunction with i.v. administered recombinant human IL-10 (rhIL-10) (25 microg/kg). In group 1, rhIL-10 was administered 2 min before endotoxin challenge; in group 2, the intervention was delayed for 1 h after endotoxin administration. rhIL-10 pretreatment reduced the LPS-induced rises in temperature and release of TNF, IL-6, IL-8, and IL-1 receptor antagonist. Endotoxin-induced granulocyte accumulation in lungs, as determined by dynamic granuloscintigrams, was prevented by rhIL-10 pretreatment, whereas granulocyte recruitment in liver and spleen was only modestly reduced. In addition, granulocyte degranulation, as measured by plasma elastase/alpha1-antitrypsin complexes, was blunted significantly by rhIL-10 pretreatment. Post-treatment with rhIL-10 did not influence LPS-induced temperature responses, cytokine release, or granulocyte degranulation. Both rhIL-10 pretreatment and post-treatment reduced LPS-induced cortisol levels. These results indicate that pretreatment with rhIL-10 reduces endotoxin-induced febrile responses, cytokine responses, and granulocyte accumulation in lungs, while in this acute model post-treatment with rhIL-10 exerts limited anti-inflammatory effects.
Enhancement of cell-mediated immunity against HIV-1 induced by coinnoculation of plasmid-encoded HIV-1 antigen with plasmid expressing IL-12.
Authors: Tsuji T , Hamajima K , Fukushima J , Xin K Q , Ishii N , Aoki I , Ishigatsubo Y , Tani K , Kawamoto S , Nitta Y , Miyazaki J , Koff W C , Okubo T , Okuda K 
Published: December 2022

Abstract
Previous investigations have demonstrated that CTL may play an important role in suppressing the disease progression of HIV infection. In this study, we inoculated mice with IL-12 expression plasmid together with plasmid-encoding HIV-1 envelope to enhance CTL activity by activating a Th1-type response. The results of delayed-type hypersensitivity using the footpad swelling response and of CTL activity clearly showed that HIV-1-specific cell-mediated immunity was enhanced by inoculation of the IL-12 expression plasmid. Quantitation of cytokine in the sera of IL-12-inoculated mice revealed that IFN-gamma significantly increased. The enhanced cell-mediated immunity responses were abrogated by combined administration of the IL-12 expression plasmid and neutralizing anti-IFN-gamma Ab. Together, these results suggest that enhanced virus-specific cell-mediated immunity occurred via an endogenously produced IFN-gamma by inoculation of IL-12 expression plasmid.
Peptide antagonists inhibit proliferation and the production of IL-4 and/or IFN-gamma in T helper 1, T helper 2, and T helper 0 clones bearing the same TCR.
Authors: Dittel B N , Sant'Angelo D B , Janeway C A 
Published: December 2022

Abstract
Engagement of a TCR by its peptide Ag bound by MHC class II molecules leads to T cell activation, resulting in proliferation and cytokine production. This agonist response can be antagonized by analogue peptides containing single amino acid substitutions. We used T cell clones isolated from a mouse transgenic for the rearranged TCR alpha- and beta-chains of the D10.G4.1 (D10) Th2 clone specific for hen egg conalbumin peptide 134-146 (CA 134-146) to characterize antagonist peptides for the D10.TCR. The D10.TCR CD4 T cell clones proliferated in a dose-dependent manner to CA 134-146, and this proliferation was accompanied by secretion of IL-4 and/or IFN-gamma with Th1, Th2, and Th0 patterns. Proliferation of the clones was inhibited completely by CA 134-146 analogue peptides containing a substitution of the glutamic acid at position 8 with alanine (E8A) or threonine (E8T). The E8A and E8T peptides also antagonized the production of mRNA and subsequent cytokine secretion of IFN-gamma and/or IL-4. Our results, showing that antagonist peptides can inhibit both T cell proliferation and cytokine production in Th1, Th2, and Th0 clones all bearing the same TCR, demonstrate that the TCR:peptide interaction determines the outcome regardless of the phenotype of the clone. Thus, antagonism by peptides acts through the TCR.
Fas ligand is positioned in mouse uterus and placenta to prevent trafficking of activated leukocytes between the mother and the conceptus.
Authors: Hunt J S , Vassmer D , Ferguson T A , Miller L 
Published: December 2022

Abstract
Despite intimate juxtaposition of maternal and fetal tissues during mammalian pregnancy, reciprocal migration of cells is limited. To evaluate the postulate that cell traffic is restricted by expression of Fas ligand (FasL) in the uterus and placenta, FasL mRNA was identified by using reverse transcription-PCR, and FasL protein was identified by Western blotting and immunohistology. FasL mRNA and protein were detected at all stages tested (gestation days (g.d.) 6-18). At g.d. 6 to 10, immunoreactive FasL was prominent in glandular epithelial cells and decidual cells. Between g.d. 12 and 14, expression shifted to placental trophoblast cells bordering maternal blood spaces and fetal placental endothelial cells. Thus, FasL is appropriately positioned, first in the uterus and then in the placenta, to deter trafficking of activated Fas+ immune cells between the mother and the fetus. To test whether the absence of functional FasL affects pregnancy, uteroplacental units from homozygous matings of gld mice, a mutant strain lacking functional FasL, were examined. Extensive leukocytic infiltrates and necrosis at the decidual-placental interface were observed from day 10 onward, resorption sites were common, and small litters were delivered by gld mice. These observations are consistent with the idea that FasL at the maternal-fetal interface protects the placenta against a maternal leukocytic influx that reduces fertility.
Developmentally ordered V-J recombination in mouse T cell receptor gamma locus is not perturbed by targeted deletion of the Vgamma4 gene.
Authors: Sunaga S , Maki K , Komagata Y , Miyazaki J , Ikuta K 
Published: December 2022

Abstract
Mouse TCR gamma genes in the gamma1 cluster are arranged in the order of Vgamma5, Vgamma2, Vgamma4, Vgamma3, Jgamma1, and Cgamma1 on the chromosome. During thymic ontogeny, each Vgamma gene recombines with the Jgamma1 gene in the order of proximity to Jgamma1. To explore the mechanism of the ordered recombination, we generated Vgamma4-deficient mice by gene targeting and the Cre/loxP system, by deleting the 4.8-kb DNA region between 3' of the Vgamma2 and 3' of the Vgamma4. In semiquantitative PCR analysis, Vgamma2-Jgamma1 recombination was detected frequently in adult thymus, while Vgamma3-Jgamma1 recombination preferentially occurred in fetal thymus of the mutant mice. There was no difference in the frequency of V-J recombinations between control and mutant mice. Southern blot analysis also revealed that recombination of the Vgamma2 gene occurred as frequently as in control mice. In addition, there was no difference in the levels of germline transcripts of Vgamma2 and Vgamma3 genes between control and mutant mice. Therefore, regulation of the Vgamma-Jgamma recombination was not affected by deletion of the Vgamma4 gene. These results suggest that the ordered recombination is controlled by regulatory elements near each Vgamma gene.
Programmed cell death of Mycobacterium avium serovar 4-infected human macrophages prevents the mycobacteria from spreading and induces mycobacterial growth inhibition by freshly added, uninfected macrophages.
Authors: Fratazzi C , Arbeit R D , Carini C , Remold H G 
Published: December 2022

Abstract
Mycobacterium avium, an opportunistic pathogen in AIDS patients, replicates in human macrophages (Mphi) and induces programmed cell death (PCD). In this study we examine the effect of freshly added, uninfected Mphi on M. avium growth in apoptotic Mphi cultures. Incubation of uninfected autologous Mphi with apoptotic Mphi infected with M. avium for 6 h results in 90% inhibition of bacterial growth. The uninfected Mphi adhere to M. avium-infected apoptotic, but not to nonapoptotic M. avium-infected Mphi, suggesting a specific interaction between apoptotic and nonapoptotic Mphi. PCD of the host Mphi also prevents the release of intracellular components and the spread of the mycobacterial infection. Once the apoptotic infected Mphi reach the necrotic stage, mycobacteria and other intracellular material are released; the latter suffice to support extracellular mycobacterial replication. Necrosis of M. avium-infected Mphi is significantly augmented by the transglutaminase inhibitors dansyl-cadaverine and cystamine, indicating that apoptosis of Mphi is dependent on the extent of cross-linking of cell proteins by transglutaminases. Consequently, transglutaminase inhibitors accelerate the release of mycobacteria and intracellular components from the infected Mphi into the medium. These findings indicate that PCD of M. avium-infected Mphi is an important defense mechanism, preventing the spread of infection by sequestering the mycobacteria and by contributing to their demise by activation of newly recruited uninfected Mphi.
The lipid A moiety of Porphyromonas gingivalis lipopolysaccharide specifically mediates the activation of C3H/HeJ mice.
Authors: Tanamoto K , Azumi S , Haishima Y , Kumada H , Umemoto T 
Published: December 2022

Abstract
The lipid A preparation isolated from Porphyromonas gingivalis was found to induce splenocyte mitogenicity and TNF-alpha release from peritoneal macrophages in LPS-unresponsive C3H/HeJ mice to the same extent as in LPS-responsive mice. In order to clarify whether the activation of C3H/HeJ mice was specifically caused by the lipid A and not by contaminating protein, two strategies were employed. The lipid A fraction from P. gingivalis was subjected to either hydrochloric acid or alkaline treatment to eliminate either glycosylated phosphate or O-acylated fatty acids from the lipid A structure, and the biologic activities of the derivatives were compared in both LPS-responsive and unresponsive C3H/HeJ mice. De-1-O-phosphorylated P. gingivalis lipid A showed partial loss, and de-O-acylated lipid A complete loss of splenocyte mitogenic and TNF-alpha-inductive activities from peritoneal macrophages in both LPS-responsive and unresponsive mice. The relative activities of the intact and treated lipid A compounds in splenocyte mitogenicity and TNF-alpha-inductive activity in macrophages were similar to the relative activities of these preparations in Limulus gelation activities. The LPS-specific antagonist, succinylated lipid A precursor, inhibited P. gingivalis lipid A-mediated splenocyte mitogenicity and TNF-alpha induction in macrophages in a similar manner in LPS-responsive and unresponsive mice. These results strongly suggest that the activation of LPS-unresponsive C3H/HeJ mice by P. gingivalis lipid A was specifically mediated by the lipid A portion and not by contaminating protein. The characteristic action of P. gingivalis lipid A on LPS-unresponsive C3H/HeJ mice was thought to reflect the unique chemical properties of this compound.
Macrophage triggering with cecropin A and melittin-derived peptides induces type II nitric oxide synthase expression.
Authors: Velasco M , Díaz-Guerra M J , Díaz-Achirica P , Andreu D , Rivas L , Boscá L 
Published: December 2022

Abstract
Triggering of RAW 264.7 cells with a cecropin A-melittin hybrid peptide (CA(1-8)M(1-18)) promoted a rapid rise in the intracellular calcium concentration that was followed, after a lag period of 6 h, by nitric oxide synthesis through the expression of the cytokine-inducible form of nitric oxide synthase (type II NOS or iNOS). The maximal effect was obtained at peptide concentrations in the 2 to 5-microM range. Simultaneous incubation with the peptide and LPS abrogated the nitric oxide synthesis elicited after LPS treatment of the cells. CA(1-8)M(1-18) induced a rapid activation of nuclear factor kappaB as evidenced by the presence of p50/p65 heterodimers of the nuclear factor kappaB/c-Rel family in the nuclei of activated cells. This peptide also activated the reporter activity of cells transfected with a plasmid harboring a 1-kb fragment corresponding to the 5'-flanking region of the murine iNOS gene. CA(1-8)M(1-18) promoted apoptotic cell death at concentrations below 1 to 2 microM, whereas higher concentrations altered the plasma membrane integrity. These results suggest the involvement of multiple intracellular signaling pathways in the mechanism by which this peptide elicits macrophage triggering.