bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stimulation of Fc(alpha) receptors induces tyrosine phosphorylation of phospholipase C-gamma(1), phosphatidylinositol phosphate hydrolysis, and Ca2+ mobilization in rat and human mesangial cells.
Authors: Gómez-Guerrero C , Duque N , Egido J 
Published: December 2022

Abstract
Although knowledge of IgA Fc receptor (Fc(alpha)R) structure and gene organization has progressed in the past few years, signal transduction pathways elicited by its activation have hardly been studied. Previously, we have demonstrated that mesangial cells (MC) possess Fc(alpha)R stimulation triggers several biologic responses. In this work, we studied the early biochemical signals triggered by Fc(alpha)R stimulation in MC. MC incubation with aggregated IgA (AIgA) elicited a dose-dependent increase in cytosolic Ca2+ ([Ca2+]i). The response was rapid and transient, and slowly fell to the original baseline. Ca2+ mobilization was dependent on the Fc region of the IgA, because Fc, but neither Fab fragment nor carbohydrates, inhibited the [Ca2+] rise. The initial induction of [Ca2+]i rise was due to Ca2+ mobilization from inositol trisphosphate (IP3)-sensitive intracellular stores, while sustained levels were maintained through extracellular Ca2+ influx. Stimulation of Fc(alpha)R also resulted in production of IP3, temporally correlated with Ca2+ mobilization. Protein tyrosine kinase inhibitors abolished [Ca2+]i rise, indicating that tyrosine phosphorylation of some substrates is required for Ca2+ mobilization. Stimulation through Fc(alpha)R gave rise to a marked increase in tyrosine phosphorylation of several proteins, including the 147-kDa band, similar in size to phospholipase C-gamma(1) (PLC-gamma(1)). Tyrosine phosphorylation of PLC-gamma(1) reached a maximum 30 s after stimulation, as determined by immunoprecipitation and Western blot. Collectively, these results indicate that the Fc(alpha)R signaling pathway in MC involves PLC-(gamma(1) activation, IP3 formation, and Ca2+ mobilization, and is linked to activation of tyrosine kinases.
Role of IL-12 in peripheral blood mononuclear cell responses to fungi in persons with and without HIV infection.
Authors: Harrison T S , Levitz S M 
Published: December 2022

Abstract
Clinical trials of IL-12 in persons infected with HIV have been proposed based on recent evidence suggesting IL-12 plays a critical role in the development of protective immune responses, and the HIV infection is associated with a deficiency of IL-12. As fungal infections are among the most common opportunistic infections associated with AIDS, we examined whether IL-12 p40 gene expression and p70 release in response to Cryptococcus neoformans and Candida albicans were deficient in monocyte-enriched PBMC from HIV-seropositive donors and whether rIL-12 could augment the proliferation of PBMC from HIV-seropositive donors in response to these fungi and to Pneumocystis carinii. PBMC from HIV-seronegative donors expressed IL-12 p40 mRNA in response to C. neoformans, C. albicans, and the positive control Staphylococcus aureus Cowan strain 1 (SAC), although the induction of IL-12 p40 mRNA was later and more prolonged with C. neoformans as the stimulus. Expression of IL-12 p40 mRNA in response to the three stimuli was similar in cells from HIV-seropositive and HIV-seronegative donors. However, when stimulated with SAC, cells from HIV-seropositive donors released significantly less IL-12, suggesting HIV infection induces a post-transcriptional defect in IL-12 release in response to SAC. While PBMC from HIV-seropositive donors had impaired proliferative responses to the three fungi tested, addition of rIL-12 did not enhance proliferation. These studies do not lend further support for the therapeutic use of IL-12 to prevent or treat fungal infections in persons infected with HIV.
Structural requirements for CD28-mediated costimulation of IL-2 production in Jurkat T cells.
Authors: Truitt K E , Nagel T , Suen L F , Imboden J B 
Published: December 2022

Abstract
Although under certain conditions an association with phosphatidylinositol 3'-kinase (PI3-K) appears to be critical for CD28 signaling, mutation of the PI3-K binding site (Tyr 170) does not alter the costimulatory ability of murine CD28 (mCD28) in Jurkat T cells. To define the structural requirements for this PI3-K-independent signaling, we expressed a series of mCD28 mutants in Jurkat. Mutation to Phe of all four cytoplasmic Tyr residues together (ALL F mutant) greatly reduced the ability of mCD28 to augment IL-2 production. Isolated re-constitution of Tyr 188, but not 170, 185, or 197, restored the ability of ALL F mCD28 to deliver a costimulus. Thus, a signal based upon Tyr 188 can deliver a costimulus for the enhancement of IL-2 production by Jurkat cells.
Phosphatidylinositol 3-kinase activation in normal human B lymphocytes.
Authors: Aagaard-Tillery K M , Jelinek D F 
Published: December 2022

Abstract
A variety of signals, mediated via either the B cell Ag receptor (BCR), or non-BCR molecules such as CD40 or cytokine receptors, have been shown to be crucial for the regulation of B cell survival, growth, and differentiation. Although it is clear that a variety of signaling pathways can be activated in B cells in a stimulus-dependent manner, it remains unknown whether differential activation of these signaling pathways is the underlying mechanism controlling B cell fate, i.e., growth vs differentiation. Initial studies reported here indicated that stimulation of highly purified peripheral blood B cells with the polyclonal B cell activators Staphylococcus aureus and CD40 ligand (CD40L) resulted in the rapid induction of phosphatidylinositol 3-kinase (PI 3-kinase) activity. Moreover, pretreatment of B cells with wortmannin, a specific inhibitor of PI 3-kinase, resulted in a complete block in induction of PI 3-kinase activity. The effects of wortmannin, as well as a second PI 3-kinase inhibitor, LY294002, on the induction of both B cell growth and differentiation were therefore investigated. Although these PI 3-kinase inhibitors variably inhibited B cell DNA synthesis in a stimulus-dependent manner, both drugs effected a near-complete block of the ability of each of these stimuli to induce Ig production. Furthermore, separation of B cells into naive IgD+ and postswitch IgD- B cells failed to reveal differential sensitivity of these populations to wortmannin. These results suggest that activation of PI 3-kinase, or other wortmannin- and LY294002-sensitive targets, is a crucial event that occurs during the differentiation of normal human B lymphocytes. The differential sensitivity of B cell responses to inhibitors of PI 3-kinase supports the notion that distinct signal transduction pathways are involved in differentiation vs proliferation of normal human B lymphocytes.
Immature stage B cells enter but do not progress beyond the early G1 phase of the cell cycle in response to antigen receptor signaling.
Authors: Carman J A , Wechsler-Reya R J , Monroe J G 
Published: December 2022

Abstract
In contrast to mature B cells, immature stage B cells do not proliferate following Ag receptor cross-linking with anti-Ig Abs. To determine where in the cell cycle immature B cells arrest, we have examined the expression of specific G, cell cycle regulators. Following surface IgM (sIgM) cross-linking on mature B cells, we observed increased expression of the early G1 kinase, cyclin-dependent kinase 4 (cdk4), and one of its regulatory subunits, cyclin D2. Mature B cells also showed increased expression of components required for G1/S transition, including cyclin E and cdk2. Whereas immature stage B cells increased expression of cyclin D2 and cdk4 after anti-IgM stimulation, unlike mature stage B cells they failed to express cyclin E and cdk2. Expression of cyclin D2 and cdk4 indicates that these cells can exit G0 and enter the initial G1 phase following sIgM ligation. Interestingly, IL-4, which by itself does not stimulate proliferation of immature B cells, induced expression of cyclin E and cdk2. These latter results suggest that IL-4 complements sIgM, signaling for proliferation by increasing the basal levels of late G1 cell cycle regulators. Consistent with this idea, IL-4 synergizes with anti-Ig Abs to promote cell cycle progression and proliferation of immature B cells. Finally, c-myc, a transcriptional regulator of some members of the cell cycle machinery, is not induced following sIgM cross-linking of immature cells. This lack of inducible expression contrasts with that seen in mature stage B cells, and in immature stage cells stimulated to proliferate with LPS. These results suggest that c-myc may be a component of the signaling pathway that induces cyclin E and cdk2 expression.
Is there a role for nitric oxide in regulation of T cell secretion of IL-2?
Authors: Marcinkiewicz J , Grabowska A , Chain B M 
Published: December 2022

Abstract
Nitric oxide (NO) can have both effector (cytotoxic) and regulatory roles in immune function. In this study, we have re-examined the potential role of nitric oxide in mediating the macrophage-dependent suppression of IL-2 synthesis. In our model, TNP-specific CD4+ T cells are cocultured with Ag and either peritoneal or alveolar macrophages. Both populations of macrophages after in vitro stimulation with IFN-gamma can inhibit IL-2 release. In vitro stimulation also induces substantial levels of NO release by these macrophages, as well as high levels of prostaglandin E2 (PGE2). However, there was no correlation between NO levels and inhibitory activity. Furthermore, NG-monomethyl-L-arginine monoacetate, a specific inhibitor of NO release had no effect on IL-2 release, while indomethacin, which blocked prostaglandin synthesis, largely abrogated the suppressor activity of both macrophage populations. Although the addition of exogenous NO donors at high concentrations could inhibit IL-2 release by T cells, our data does not support the hypothesis that NO is a major macrophage mediator of suppression in this model.
An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents cell death in vitro.
Authors: Papoff G , Cascino I , Eramo A , Starace G , Lynch D H , Ruberti G 
Published: December 2022

Abstract
Fas/Apo-1 molecule, also designated as CD95, is a member of the TNF receptor family. Fas cross-linking by its natural ligand or by agonistic mAbs results in rapid induction of apoptosis in susceptible cells. in addition to the Fas full-length mRNA, human activated PBMC and tumor cell lines express several mRNA Fas variants that derive from alternative splicing of the primary transcript. All five variants identified, two of which are newly described here, code for soluble proteins that, with the exception of FasTMDel, are truncated in the extracytoplasmic region and possess short C-terminal amino acid sequences corresponding to a different reading frame. We have identified Abs that recognize all splicing variants and established a sandwich ELISA by which the soluble Fas molecules could be detected in culture supernatants of transfected cell lines and in PBMC following T cell activation. Next, we have studied in detail the functional role of these variants by apoptosis inhibition studies. We found that all soluble proteins block the apoptosis induced by either an agonistic Ab or, more importantly, by the natural Fas ligand in Fas-positive sensitive cell lines. interestingly, this functional property can be assigned to the first 49 amino acids of the mature protein that is the only region shared by the five soluble Fas molecules.
Possible involvement of C5/C5a in the efferent and elicitation phases of contact sensitivity.
Authors: Tsuji R F , Kikuchi M , Askenase P W 
Published: December 2022

Abstract
The elicitation of 24-h contact sensitivity (CS) in mice requires a serotonin-dependent, 2-h response called CS initiation. We studied the role of complement (C) by comparing CS in DBA/1 (C5-normal) vs DBA/2 (C5-deficient) mice and found impaired 2-h, but not 24-h, CS. We showed previously that 2-h responses represent CS initiation and are required for elicitation of 24-h responses. Treatment of C5-deficient mice with absent macroscopic responses (ear swelling) with a selective serotonin antagonist inhibited 24-h CS, suggesting that C5-deficient mice had submacroscopic (i.e., microscopic), serotonin-dependent CS initiation. When normal mouse serum was used as a source of C5 to reconstitute C5-deficient mice, significant 2-h responses were restored. Furthermore, heat treatment of normal mouse serum to inactivate C abrogated restoration of 2-h responses. Thus, C5 was suggested to be involved in CS initiation. Using a suboptimal immunizing dose of Ag revealed an impaired 24-h component of CS in DBA/2 mice, but not in DBA/1 mice, and also in C5-deficient B10.D2/o mice compared with C5-normal B10.D2/n mice with a suboptimal eliciting dose of Ag. Again, reconstitution of B10.D2/o mice with normal mouse serum restored deficient 24-h CS responses. Thus, 2-h and classical 24-h CS probably depend in part on C5. These results imply that C5 may play a role in the elicitation of 24-h CS, probably via required preceding CS initiation.
C-reactive protein binds to a novel ligand on Leishmania donovani and increases uptake into human macrophages.
Authors: Culley F J , Harris R A , Kaye P M , McAdam K P , Raynes J G 
Published: December 2022

Abstract
C-reactive protein (CRP) is a major acute phase protein of man, with serum concentrations increasing dramatically following stimulation of hepatocytes by inflammatory cytokines. However, the role of CRP in inflammation and resistance to infection is still poorly understood. Here, the specificity of CRP binding to the surface of Leishmania donovani, an obligate intracellular parasite of mononuclear phagocytes, is described. CRP is shown to bind to promastigotes at the infectious metacyclic stage of development, at concentrations found in normal human serum. The presence of CRP on the surface of promastigotes substantially increases uptake into human monocyte-derived macrophages. Unusually, CRP does not bind via its characteristic ligand, phosphorylcholine. We show that CRP binds to the lipophosphoglycan (LPG) component of the promastigote cell surface, a molecule implicated in both uptake and survival of these parasites within the macrophage, and also to the major secreted protein of promastigotes, secreted acid phosphatase. Using mAb to LPG with known ligand specificities, we define a novel ligand for CRP as the repeating phosphorylated disaccharide units that form the backbone of LPG.
Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity.
Authors: King C L , Medhat A , Malhotra I , Nafeh M , Helmy A , Khaudary J , Ibrahim S , El-Sherbiny M , Zaky S , Stupi R J , Brustoski K , Shehata M , Shata M T 
Published: December 2022

Abstract
Humans chronically infected with schistosomiasis usually have impaired parasite Ag-specific lymphocyte proliferation and IFN-gamma production that may facilitate persistence of the parasite while producing little clinical disease. The mechanisms that contribute to the immunologic hyporesponsiveness in these patients remain undefined. IL-10 has been shown to exert an inhibitory effect on cell-mediated immunity. To determine whether endogenous IL-10 has a role in regulating parasite-specific anergy in schistosomiasis, neutralizing anti-IL-10 added to PBMC from Schistosoma haematobium patients' enhanced adult worm (SWAP)- or egg Ag (SEA)-driven lymphocyte proliferation and/or IFN-gamma production by 2- to &gt;100-fold in 32 of 38 subjects. In contrast, anti-IL-10 failed to significantly augment the mycobacterial Ag, purified protein derivative (PPD)-driven lymphocyte proliferation, or IFN-gamma production in 9 or 10 of 14 individuals, respectively. SWAP or SEA triggered IL-10 release from PBMC of both patients and healthy individuals; however, CD4+ cells were a significant source of IL-10 only in infected subjects. PPD relative to SWAP induced fivefold less IL-10 release by CD4+ cells (p &lt; 0.01). A possible mechanism whereby IL-10 suppressed Ag-specific T cell responses was demonstrated by the ability of SWAP and not PPD to suppress B7 expression on PBMC. Anti-IL-10 completely inhibited the parasite Ag-induced down-regulation of B7 expression. These studies indicate that IL-10 contributes to parasite Ag-induced T cell hyporesponsiveness observed in patients with chronic schistosomiasis hematobia.
Relation of oxidative stress and glutathione synthesis to CD95(Fas/APO-1)-mediated apoptosis of adult T cell leukemia cells.
Authors: Kohno T , Yamada Y , Hata T , Mori H , Yamamura M , Tomonaga M , Urata Y , Goto S , Kondo T 
Published: December 2022

Abstract
An IL-2 dependent adult T cell leukemia cell line (SO4) has been established that is sensitive to CD95-mediated apoptosis as well as a subline (R-SO4) that is resistant. Incubating SO4 cells with anti-CD95 IgM mAb caused concentration-dependent cell death. On the contrary, R-SO4 cells did not die even at 1000 ng/ml of anti-CD95 IgM mAb. The levels of CD95 expression on R-SO4 cells were one-third of those on SO4 cells. However a blocking Ab, anti-CD95 IgG mAb, did not induce complete resistance of SO4 cells to anti-CD95 IgM mAb as R-SO4 cells. As CD95 and TNF receptor are similar, and TNF/TNF receptor binding induces oxygen radicals, the involvement of oxidant and antioxidant systems in CD95-mediated apoptosis has been examined. The addition of anti-CD95 IgM mAb resulted in formation of intracellular oxygen radical species in the SO4 cells as measured using 2',5',-dichlorofluorescein as substrate. The oxygen radical production induced DNA damage as determined by formation of 8-hydroxydeoxyguanosine. No increase in the formation of oxygen radicals was observed in R-SO4 cells. Concentrations of the intracellular antioxidant, glutathione, and the key enzyme for its synthesis, gamma-glutamylcysteine synthetase, were 150% increased in R-SO4 cells in comparison with that of SO4 cells. Moreover, glutathione ester decreased the formation of 8-hydroxydeoxyguanosine. These results suggested that apoptosis mediated by CD95 in ATL cells is related to the production of oxygen radical species and cellular antioxidant systems, especially, glutathione synthesis.
Helicobacter-specific cell-mediated immune responses display a predominant Th1 phenotype and promote a delayed-type hypersensitivity response in the stomachs of mice.
Authors: Mohammadi M , Czinn S , Redline R , Nedrud J 
Published: December 2022

Abstract
Studies regarding the nature of cell-mediated immunity in Helicobacter pylori infection and its role in pathogenesis have yielded controversial results. To address this issue in a controlled manner, we have employed the well-characterized Helicobacter felis-mouse model. Immunized/challenged and nonimmunized/infected mice were evaluated for cellular proliferation, gastric inflammation, and cytokine and Ab production at various times after infection. We observed two types of cell-mediated immune responses depending on the nature of the Ag preparation. The first response is a Helicobacter-independent response, present in all experimental groups, which is directed toward Ags such as urease and heat shock proteins. The second is a Helicobacter-dependent cellular response restricted to mice previously exposed to Helicobacter Ags either by immunization or infection. This response was not seen in noninfected controls. The Helicobacter-dependent cellular response had a Th1 phenotype, as either infected or immunized/challenged mice demonstrated local and systemic production of IFN-gamma and undetectable levels of IL-4 or IL-5. Cellular proliferation correlated with the severity of gastric inflammation in both immunized/challenged (protected) and nonimmunized/infected mice. Finally, in vivo neutralization of IFN-gamma resulted in a significant reduction of gastric inflammation in H. felis-infected, as well as immunized/challenged, mice. This treatment also revealed the presence of Th2 cells, restricted to immunized/challenged mice, as demonstrated by local and systemic production of IL-4 in these mice. These data demonstrate that Helicobacter infection and/or immunization stimulate a predominantly Th1-type, Ag-specific response and promote a local delayed-type hypersensitivity response in the stomach that may be inhibited by depletion of IFN-gamma.
Dissection of CR1, factor H, membrane cofactor protein, and factor B binding and functional sites in the third complement component.
Authors: Lambris J D , Lao Z , Oglesby T J , Atkinson J P , Hack C E , Becherer J D 
Published: December 2022

Abstract
Previous studies have suggested that the residues 727-768 of human (Hu) C3 contain the binding sites for CR1, factor H, and factor B. Here, we have (1) characterized further some of the C3 structural requirements for its binding to CR1, H, and B, (2) investigated the functions associated with these C3-ligand interactions, and (3) studied the relationship of MCP-binding sites in C3 with those for CR1, H, and B. Hu C3 molecules in which residues 727-768 were deleted (designated C3delta727-768) or substituted with the corresponding segment of cobra venom factor, Xenopus, or trout C3 (chimeric C3s) were expressed in the baculovirus system and analyzed for their reactivity with C3-binding proteins. In contrast to wild-type iC3 which, in the presence of CR1, is cleaved by factor I to iC3b-a and C3c-a and C3dg, all chimeric C3s were cleaved only to iC3b-a. In addition, the cleavage of deleted (C3delta727-768) iC3 to iC3b-a by factor I in the presence of CR1 was significantly reduced, whereas it remained unaltered in the presence of MCP. Cleavage of iC3 to iC3b-a by factor I and H was similar in all expressed C3s except C3delta727-768, whose cleavage was significantly reduced. All of the expressed molecules except C3delta727-768 were capable of forming the fluid-phase alternative pathway C3 convertase, and all reacted with properdin. These results suggest that during cleavage of iC3 by factor I and CR1, or H, CR1 and H bind to at least two sites on C3 and that the MCP binding site(s) on C3b are different from those for CR1. They also indicate that some or all of the C3 residues that are directly involved in, or contribute to, the structure of one of the CR1 and H binding sites are located within residues 727-768. These studies also demonstrate that, although this segment of C3 may be involved in C3-factor B interaction, other residues in addition to 736EE (previously implicated in B binding) must also contribute significantly to this interaction.