bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autologous dendritic cells or cells expressing both B7-1 and MUC1 can rescue tumor-specific cytotoxic T lymphocytes from MUC1-mediated apoptotic cell death
Authors: Kontani Keiichi , Taguchi Osamu , Narita Tatsuhiko , Hiraiwa Nozomu , Sawai Satoru , Hanaoka Jun , Ichinose Masutaro , Tezuka Noriaki , Inoue Shuhei , Fujino Shozo , Kannagi Reiji 
Published: September 2022

AbstractWe attempted to induce MUC1-specific cytotoxic T lymphocytes (CTLs) by mixed-lymphocyte tumor cell culture (MLTC) using two allogeneic MUC1-positive cancer cell lines, T-47D and MCF7. The induced CTLs exhibited MUC1-specific cytotoxicity 16 days after the initial stimulation. However, these CTLs underwent apoptotic death within 16 days. To examine whether the B7-1 molecule is required for the expansion of the responder cells, a B7-1(+)/MUC1(-) cell line was transfected with MUC1 cDNA, and the resulting transfectant was employed as a stimulator in an autologous MLTC. The CTLs exhibited MUC1 specificity but also continued to propagate. In parallel, autologous dendritic cells (DCs) were added to an MLTC containing peripheral blood lymphocytes (PBLs) and the allogeneic MUC1-positive stimulators. The CTLs demonstrated MUC1 specificity and their number increased. This suggests that the B7-1 molecule is required for rescuing CTLs from MUC1-mediated apoptotic death, but not for the induction of MUC1-specific responsiveness. This strategy to obtain the CTLs efficiently may be useful for adoptive immunotherapy against cancer.
Combined inhibition of indoleamine 2,3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-γ-activated macrophages
Authors: Chiarugi Alberto , Sbarba Persio Dello , Paccagnini Alessandro , Donnini Sandra , Filippi Sandra , Moroni Flavio 
Published: September 2022

Abstract
We evaluated the synthesis of nitric oxide (NO) and of the neurotoxic kynurenine metabolites 3OH-kynurenine and quinolinic acid (QUIN) in interferon-γ (IFN-γ)-activated macrophages of the murine BAC1.2F5 cell line with the aim of investigating the roles of mononuclear phagocytes in inflammatory neurological disorders. IFN-γ induced indoleamine 2,3-dioxygenase (IDO) and NO synthase (NOS) and increased the synthesis of 3OH-kynurenine, QUIN, and NO that accumulated in the incubation medium where they reached neurotoxic levels. Macrophage exposure to norharmane, an IDO inhibitor, resulted in a decreased formation of not only the kynurenine metabolites but also NO. The inhibition of NO synthesis could not be ascribed to reduced NADPH availability or decreased NOS induction. Norharmane inhibited NOS activity also in coronary vascular endothelial cells and in isolated aortic rings. Our findings suggest that activated macrophages release large amounts of neurotoxic molecules and that norharmane may represent a prototype compound to study macrophage involvement in inflammatory brain damage.
TNF-α-mediated neutrophil apoptosis involves Ly-GDI, a Rho GTPase regulator
Authors: Kettritz Ralph , Xu Ya-Xin , Faass Bettina , Klein Jon B , Müller Eva C , Otto Albrecht , Busjahn Andreas , Luft Friedrich C , Haller Hermann 
Published: September 2022

Abstract
We investigated intracellular signaling events involved in fibronectin-accelerated TNF-α-mediated PMN apoptosis by means of 2-D gel electrophoresis and western blotting. Proteins were sequenced with electrospray ionization mass spectrometry. Apoptosis was quantitated by flow cytometry. We detected a cluster of acidic, high molecular-weight proteins that were only tyrosine phosphorylated when TNF-α-treated PMN interacted with fibronectin. Sequence analysis revealed that one of these proteins was Ly-GDI, a regulator of Rho GTPases. Fibronectin increased the TNF-α-induced Ly-GDI cleavage, yielding a 23-kD fragment. At 8 h, intact Ly-GDI was decreased to 33% on fibronectin, compared with 69% on PolyHema (P&lt;0.05). Inhibition of tyrosine phosphorylation prevented phosphorylation of Ly-GDI, fibronectin-accelerated Ly-GDI cleavage, and fibronectin-accelerated apoptosis in TNF-α-treated PMN. We found that Ly-GDI cleavage was dependent on caspase-3 activation and that caspase-3 inhibition decreased apoptosis. We conclude that tyrosine phosphorylation of Ly-GDI, followed by increased caspase-3-mediated Ly-GDI cleavage, is a signaling event associated with accelerated TNF-α-mediated apoptosis on fibronectin.
The level of HIV infection of macrophages is determined by interaction of viral and host cell genotypes
Authors: Cunningham A L , Li S , Juarez J , Lynch G , Alali M , Naif H 
Published: September 2022

Abstract
The outcome of HIV infection in vivo and in vitro depends on the interaction of viral and cellular genotypes. Analysis of infection of blood monocyte-derived macrophages by primary HIV strains shows that approximately one-third of 32 isolates was consistently high-replicating, one-third was consistently low-replicating, and one-third was dependent on the donor of the macrophages (i.e., variable). HIV isolates from patients with AIDS showed enhanced replication within macrophages and predominant use of CCR5 for entry, although 13% did use CXCR4. Tissue isolates from brain and CSF showed an enhanced ability to infect 1-day-old monocytes compared with blood isolates from patients with AIDS. The ability of primary isolates to infect neonatal or adult monocytes maturing into macrophages or placental macrophages correlated directly with the extent of CCR5 expression. Studies of macrophages from pairs of identical twins and unrelated donors showed genetic control over CCR5 expression, which was independent of the CCR5▵32 genotype. Furthermore, these studies showed a marked host-cell genetic effect on the variable primary HIV strains. Although CCR5 was essential for the entry of most primary isolates, it was not the essential “bottleneck” determining productivity of infection. The location of this bottleneck in the HIV replication cycle differs according to viral strain and host-cell donor, but it was exerted before the stage of reverse transcription in 80–90% of cases. Such host-cell genetic factors may affect viral load in vivo where macrophages are the predominant target cells.
The emerging role of CD40 ligand in HIV infection
Authors: Kornbluth Richard S 
Published: September 2022

AbstractCD40 ligand (also called CD40L, CD154, or TNFSF5) is a membrane protein expressed mainly by activated CD4+ T cells, which interacts with its receptor, CD40, on a variety of cells. The crucial importance of the CD40L-CD40 system for many immune responses has been extensively described. This review focuses on the multiple roles that this system may play in HIV infection. In early HIV infection, CD40L expression contributes to the immunological control of viral replication by inducing HIV-suppressive chemokines and supporting the production of anti-HIV antibodies and cytotoxic T cells. However, by activating antigen-presenting cells, such as dendritic cells and macrophages, CD40L can also lead to increased CD4+ T cell activation, which promotes the replication of HIV in these lymphocytes. Later, with the development of AIDS, CD40L-expressing CD4+ T cells become selectively depleted, perhaps as a result of a gp120-induced signal through CD4 that down-regulates CD40L expression. This acquired CD40L deficiency may explain the similarity between the types of opportunistic infections that occur in AIDS and in congenital CD40L deficiency. Vaccines or other strategies that promote the growth of CD4+ T cells capable of expressing CD40L may help to sustain host immunity against HIV and prevent AIDS-defining opportunistic infections.
Macrophage-derived chemokine (MDC)
Authors: Mantovani Alberto , Gray Patrick A , Van Damme Jo , Sozzani Silvano 
Published: September 2022

AbstractMacrophage-derived chemokine (MDC) is a CC chemokine paradigmatic of emerging aspects of chemokine immunobiology. It is constitutively expressed, yet microbial products and cytokines regulate its expression with divergent effects of type II (IL-4 and IL-13) and type I (interferon) cytokines. Processing of the mature protein by dipeptidyl peptidase IV/CD26 provides a further level of regulation. It acts on diverse cellular targets including dendritic cells (DC), NK cells, and T cell subsets. Among these, MDC is a potent attractant for CCR4 expressing polarized Th2 and Tc2 cells, and evidence is consistent with a role of this chemokine as an amplification loop of polarized type II responses. Emerging indications on the involvement of MDC in diverse pathologies, ranging from allergic reactions to HIV infection and neoplasia, are discussed.
Leptin in the regulation of immunity, inflammation, and hematopoiesis
Authors: Fantuzzi Giamila , Faggioni Raffaella 
Published: September 2022

Abstract
Leptin, the product of the ob gene, is a pleiotropic molecule that regulates food intake as well as metabolic and endocrine functions. Leptin also plays a regulatory role in immunity, inflammation, and hematopoiesis. Alterations in immune and inflammatory responses are present in leptin- or leptin-receptor-deficient animals, as well as during starvation and malnutrition, two conditions characterized by low levels of circulating leptin. Both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines. Leptin exerts proliferative and anti-apoptotic activities in a variety of cell types, including T lymphocytes, leukemia cells, and hematopoietic progenitors. Leptin also affects cytokine production, the activation of monocytes/macrophages, wound healing, angiogenesis, and hematopoiesis. Moreover, leptin production is acutely increased during infection and inflammation. This review focuses on the role of leptin in the modulation of the innate immune response, inflammation, and hematopoiesis.
The protective effect of IFN-γ in experimental autoimmune diseases: a central role of mycobacterial adjuvant-induced myelopoiesis
Authors: Matthys Patrick , Vermeire Kurt , Heremans Hubertine , Billiau Alfons 
Published: September 2022

AbstractThe study of animal models for organ-specific autoimmune disease contributes to our understanding of human diseases such as multiple sclerosis and rheumatoid arthritis. Although experimental autoimmune diseases develop spontaneously in certain strains of mice, others need to be induced by administration of organ-specific autoantigen, often together with complete Freund’s adjuvant (CFA), containing heat-killed mycobacteria. In the two types of models, the role of endogenous interferon-γ (IFN-γ) has extensively been investigated by using neutralizing anti-IFN-γ antibodies and by employing mice genetically deficient in IFN-γ or its receptor. In these studies disease-promoting as well as disease-protective roles of endogenous IFN-γ have been described. Remarkably, in most models that rely on the use of CFA, there is abundant evidence for a protective role. Here, we review evidence that this role derives from an inhibitory effect of IFN-γ on myelopoiesis elicited by the killed mycobacteria. These findings explain the bimodal role of IFN-γ in different models of autoimmune disease and raise questions regarding the clinical relevance of these models.
Impaired splenic erythropoiesis in phlebotomized mice injected with CL2MDP-liposome: an experimental model for studying the role of stromal macrophages in erythropoiesis
Authors: Sadahira Yoshito , Yasuda Tatsuji , Yoshino Tadashi , Manabe Toshiaki , Takeishi Toshiyuki , Kobayashi Yoshiaki , Ebe Yusuke , Naito Makoto 
Published: September 2022

Abstract
Erythropoiesis occurs in the presence of erythropoietin (EPO) without macrophages in vitro. In hematopoietic tissues, however, erythroid cells associate closely with stromal macrophages, forming erythroblastic islands via interactions with adhesion molecules. To elucidate the role of macrophages in erythropoiesis, we selectively abrogated stromal macrophages of splenic red pulp of phlebotomized mice by injection with dichloromethylene diphosphonate encapsulated in multilamellar liposomes (CL2MDP-liposome). In the spleen, no erythropoietic activity occurred until 5 days after the treatment. Colony assay revealed that the erythropoiesis was suppressed at the level of CFU-E. The splenic erythropoietic activity gradually developed from day 6 after the treatment, when F4/80+ macrophages began to appear in the red pulp. EPO mRNA was expressed in kidney but not in liver or spleen of phlebotomized mice injected with CL2MDP-liposome, and the serum EPO concentration in these mice was higher than that in phlebotomized mice. These findings suggest that abrogation of stromal macrophages by injection with CL2MDP-liposome impairs the splenic microenvironment for erythropoiesis induced by hypoxic stress, and this may be an excellent experimental model for further characterization of the in vivo role of splenic macrophages in erythropoiesis.
Migration of dermal cells expressing a macrophage C-type lectin during the sensitization phase of delayed-type hypersensitivity
Authors: Chun Kyung-hee , Imai Yasuyuki , Higashi Nobuaki , Irimura Tatsuro 
Published: September 2022

Abstract
Dermal cells expressing a macrophage C-type lectin (mMGL) were previously suggested to migrate to regional lymph nodes during the sensitization phase of delayed-type hypersensitivity (DTH). The migration seemed to be induced by the solvent used to dissolve the antigen, and the DTH response was significantly enhanced by the migration. In this study, immunohistochemical analysis of skin after epicutaneous application of one of such solvents, a mixture of acetone and dibutylphthalate (AD), revealed a transient decrease in the number of mMGL-positive cells in the dermis. A similar decrease in this cell population was also observed in an ex vivo assay with skin explants excised from AD-treated sites. Conditioned medium from organ culture of AD-treated skin induced a similar decrease of mMGL-positive cells in untreated dermis, indicating the involvement of soluble factors. mMGL-positive cells seemed to represent a unique subpopulation of F4/80-positive dermal cells.
Altered membrane trafficking in activated bone marrow-derived macrophages
Authors: Tsang Albert W , Oestergaard Kirsten , Myers Jesse T , Swanson Joel A 
Published: September 2022

Abstract
Activation of macrophages with interferon-γ (IFN-γ) and lipopolysaccharide (LPS) leads to increased intracellular resistance to microbes and increased major histocompatibility complex class II-restricted antigen presentation, processes that both use the vacuolar compartment. Despite the requirement of the macrophage vacuolar compartment for microbicidal activities and antigen processing, the rates of endocytosis and membrane trafficking in activated macrophages are not clearly defined. In this study, vacuolar compartment dynamics were analyzed in murine bone marrow-derived macrophages activated with LPS and/or IFN-γ, conditions that increased macrophage nitric oxide production and resistance to infection by Listeria monocytogenes. Relative to nonactivated cells, activated macrophages showed diminished rates of fluid-phase pinocytosis and phagocytosis and delayed progression of macropinosomes and phagosomes to late endosomes and lysosomes. In contrast to the slowing of membrane trafficking, rates of macropinosome acidification were similar between activated and nonactivated cells. One consequence of this slowed membrane trafficking in activated macrophages was a prolonged exposure of incoming molecules to an acidic nonlysosomal compartment, a condition which may facilitate microbicidal chemistries or antigen processing.
Engagement of β2 integrins induces surface expression of β1 integrin receptors in human neutrophils
Authors: Werr Joachim , Eriksson Einar E , Hedqvist Per , Lindbom Lennart 
Published: September 2022

AbstractInduction of β1 integrin (CD49/CD29) expression in polymorphonuclear leukocytes (PMN) has been shown to be associated with transendothelial migration recently. Yet, β1 integrin expression is relatively insensitive to cell activation with soluble agonists, such as N-formyl-methionyl-leucyl-phenylalanine (fMLP). We hypothesized that β2 integrins (CD11/CD18), critically involved in PMN adhesion and extravasation, may play a role in regulating β1 integrin expression in PMN. Antibody cross-linking of CD18, mimicking adhesion-dependent engagement of β2 integrins, resulted in rapid, tyrosine kinase-dependent upregulation of β1 integrins. This response was potentiated by simultaneous chemoattractant (fMLP) stimulation of PMN. Moreover, upregulation of β1 integrins evoked by CD18 cross-linking was found to support adhesion of fMLP-stimulated PMN to matrix proteins and also was critical for the ability of PMN to migrate in collagen gels in response to a gradient of fMLP. Taken together, these data demonstrate that engagement of β2 integrins in human PMN induces β1 integrin expression in these cells of significance for their migration in the extravascular tissue. Thus, β2 integrins may serve the function to regulate PMN locomotion in extravascular tissue via receptor crosstalk with β1 integrins.
Differential expression of the chemokine receptors by the Th1- and Th2-type effect or populations within circulating CD4+ T cells
Authors: Yamamoto Junko , Adachi Yuichi , Onoue Yoichi , Adachi Yoko S , Okabe Yoshie , Itazawa Toshiko , Toyoda Masahiko , Seki Taisuke , Morohashi Masaaki , Matsushima Kouji , Miyawaki Toshio 
Published: September 2022

Abstract
The in vitro studies have proposed that human Th1 cells favor expression of CXCR3 or CCR5, whereas Th2 cells favor CCR3 and CCR4. In this study, the in vivo relevance of expression of these chemokine receptors on Th cells was investigated in patients with atopic dermatitis (AD) as the Th2-dominated disorder and nonatopic normal individuals. Flow-cytometric analysis using monoclonal antibodies against CXCR3, CCR5, CCR3, and CCR4 disclosed that a substantial proportion of memory (CD45RO+) CD4+ T cells in the blood of AD and normal patients expressed CXCR3, CCR5, or CCR4, but expression of CCR3 on these cells was negligible. Stimulation studies combined with intracellular cytokine staining revealed that the cells capable of producing Th2 cytokines, such as interleukin-4 (IL-4), IL-5, and IL-13, were restricted to the CCR4-expressing population within memory CD4+ T cells. Concerning Th1 cytokine production, interferon-γ (IFN-γ)-producing cells resided exclusively in CXCR3-expressing memory CD4+ T cells, although IFN-γ production was found in both memory CD4+ T cells with and without CCR5 expression. We observed that CCR4-expressing memory CD4+ T cells in the blood were more increased in AD patients as compared with normal patients, whereas CXCR3-expressing memory CD4+ T cells were present in a lower frequency in AD than seen in normal patients. These results suggest that CXCR3 and CCR4, but not CCR5 or CCR3, appear to serve as the useful markers for identification of circulating Th1 and Th2 effector populations.
Linomide abolishes leukocyte adhesion and extravascular recruitment induced by tumor necrosis factor αin vivo
Authors: Zhang Xiao Wei , Hedlund Gunnar , Borgström Per , Arfors Karl E , Thorlacius Henrik 
Published: September 2022

AbstractThe immunomodulator Linomide (roquinimex) ameliorates the development of numerous inflammatory and immunological diseases, including sepsis, arthritis, and encephalomyelitis. However, the mechanism underlying this protective effect of Linomide remains unclear. In this study, we wanted to evaluate the effect of Linomide treatment on the different steps in the extravasation process of leukocytes stimulated by tumor necrosis factor α (TNF-α) in vivo. For this purpose, we used intravital microscopy in the mouse cremaster muscle microcirculation. We found that pretreatment with Linomide dose-dependently (3–300 mg/kg) reduced TNF-α-induced leukocyte adhesion and tissue recruitment. Notably, at 300 mg/kg of Linomide, the leukocyte response to TNF-α was nearly abolished, i.e. leukocyte adhesion was decreased by 83% and recruitment by 86%. In fact, the anti-inflammatory effect of this dose of Linomide corresponded in magnitude to the potency of 10 mg/kg of dexamethasone. Moreover, administration of Linomide did not alter the systemic leukocyte counts. On the other hand, 1–10 mg/kg of dexamethasone decreased the circulating number of mononuclear leukocytes by 77%. Taken together, our novel findings demonstrate that Linomide is a potent inhibitor of leukocyte adhesion and recruitment in cytokine-activated tissues. These data may help explain the documented protection provided by Linomide in inflammatory diseases characterized by cytokine activation and leukocyte accumulation.
αMβ2 (CD11b/CD18, Mac-1) integrin activation by a unique monoclonal antibody to αM I domain that is divalent cation-sensitive
Authors: Orchekowski Randal P , Plescia Janet , Altieri Dario C , Bajt Mary Lynn 
Published: September 2022

AbstractThe β2 (CD18) leukocyte integrins play a key role in normal and inflammatory immune responses. In resting leukocytes, these receptors do not bind ligands. However, when leukocytes are exposed to an appropriate agonist, high-affinity ligand binding is achieved, presumably as a result of conformational changes in the integrin. In this study, we describe a novel monoclonal antibody, mAb 6C1, directed against the αM subunit, which directly induces adhesion of αMβ2-transfected CHO cells to fibrinogen, ICAM-1, and iC3b. Induction of binding could also be accomplished by monovalent Fab fragments of mAb 6C1 at concentrations similar to that observed with intact IgG, demonstrating stimulation of adhesion was not because of receptor cross-linking at the cell surface. The binding of mAb 6C1 induces conformational changes in the receptor, as evidenced by the expression of an “activation reporter” epitope recognized by mAb 24. The binding of mAb 6C1 is modulated by divalent cations. Mn2+ promoted high levels of 6C1 binding, and Mg2+ supported low levels of binding, however Ca2+ failed to support binding. A unique distinction of mAb 6C1 is localization of its epitope to the αM I domain. The αM I domain is essential for ligand binding, can directly bind divalent cations, and participates in the regulation of αMβ2 ligand-binding affinity. Thus, these studies have identified a novel αM I domain activation epitope of αMβ2 and support the idea that the I domain modulates the activational state of the β2 integrins.
Fas activation reduces neutrophil adhesion to endothelial cells
Authors: Greenstein Stephanie , Barnard Joseph , Zhou Kairong , Fong Miranda , Hendey Bill 
Published: September 2022

Abstract
Polymorphonuclear neutrophils (PMN) express apoptotic markers and lose effector functions including adhesion, chemotaxis, and phagocytosis when cultured overnight. Although the loss of function correlates with apoptosis, it is not clear if functions are lost before an early marker of apoptosis, the display of phosphatidylserine (PS), targets PMN for removal by phagocytic cells. To address this question, freshly isolated PMN were treated with Fas-activating antibodies to induce apoptosis rapidly. Early markers of apoptosis and PMA-stimulated adhesion to endothelial cells were measured. After 1 h of Fas exposure, only 16% PMN had externalized PS. In contrast, Fas activation reduced PMA-stimulated adhesion between 68 and 27% depending on PMA concentration. The loss of adhesion was accompanied by a reduction in β2 integrin expression and receptor clustering. These results indicate that the Fas-induced loss of adhesion may precede PS externalization and could limit participation in the inflammatory response before PS externalization targets PMN for removal.