bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiological activation of human neutrophils down-regulates CD53 cell surface antigen
Authors: Mollinedo Faustino , Martín-Martín Belén , Gajate Consuelo , Lazo Pedro A
Published: January 2018

Tetraspanin transmembrane proteins have a metastasis suppressor effect by acting as cell motility brakes in tumor cells. CD53 is a panleukocyte antigen that belongs to the tetra-span superfamily. Human neutrophils express high levels of CD53. We tested the hypothesis that this antigen level changes when cells are activated. Treatment of human neutrophils with their physiological activators, tumor necrosis factor α or platelet-activating factor, resulted in down-regulation of this antigen from the cell surface, as assessed by immunofluorescence flow cytometry. Similar responses were observed when neutrophils were stimulated with chemotactic N-formyl-methionyl-leucyl-phenylalanine, phorbol ester, or the calcium ionophore ionomycin. The CD53 antigen down-regulation upon neutrophil stimulation was further confirmed by immunoblotting analysis and was not correlated with a change in the level of CD53 transcripts. This CD53 antigen down-regulation paralleled that of CD43 and CD44 antigens in these cells, despite their different protein structure. The down-regulation of the three antigens CD53, CD43, and CD44 could be inhibited by phenylmethylsulfonyl fluoride, suggesting that CD53 antigen down-regulation is the result of the activation of a proteolytic mechanism. Down-regulation of CD53 antigen level, as a result of cellular stimulation, might play a role in the different aspects of neutrophil biology, by modulating its interactions on the cell surface.
Blocking cytokines with genes
Authors: Evans C H , Ghivizzani S C , Robbins P D
Published: January 2018

The pathophysiology of rheumatoid arthritis (RA) is primarily driven by proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α. Several biological agents have been identified that effectively block the activity of these cellular messengers, and administration of these agents to animal models of RA and human patients has been found to have therapeutic benefit. The application of gene therapy for the treatment of RA and other articular diseases is being explored to overcome current limitations with delivery of therapeutics to joint tissues. To date, laboratory research has focused on two main areas: (1) evaluation of gene delivery approaches and (2) identification of therapeutic gene products. Considerable progress has been reported with the use of local gene delivery to synovial cells by both in vivo and ex vivo methods and by systemic administration of gene delivery vectors via the circulation. Gene products that have therapeutic efficacy in animal models of RA include: IL-1 receptor antagonist, soluble IL-1 receptor I, soluble tumor necrosis factor receptor II, viral IL-10, and transforming growth factor β, among others. The success of these laboratory studies has led to the implementation of a Phase I clinical trial to asses the safety and feasibility of using gene therapy in the treatment of RA. J. Leukoc. Biol. 64: 55–61; 1998.
Molecular mimicry of the inflammation modulatory proteins (IMPs) of poxviruses: evasion of the inflammatory response to preserve viral habitat
Authors: Howard Jeremy , Justus David E , Totmenin Alexei V , Shchelkunov Sergei , Kotwal Girish J
Published: January 2018

Microorganisms encode numerous immunomodulators that resemble, in structure and function, molecules captured over the millennia from their hosts [G. J. Kotwal J. Leukoc. Biol. 62, 415–429]. The vaccinia virus complement control protein (VCP) was the first soluble microbial protein to have a postulated role in the immunomodulation and evasion of host defense [G. J. Kotwal and B. Moss Nature 355, 176–179]. Purified bioactive VCP has been shown to bind to C3 and C4, block the complement cascade at multiple sites [G. J. Kotwal et al. Science 250, 827–830; R. Mckenzie, G. J. Kotwal et al. J. Infect. Dis. 166, 1245–1250] and exhibit a greater potency than the human complement 4b binding protein, C4b-BP [G. J. Kotwal, Am. Biotech. Lab. 9,76]. The importance of this protein to poxviruses was further demonstrated in rabbits and guinea pigs through the use of recombinant virus lacking an intact DNA coding for VCP [Isaacs, G. J. Kotwal, and B. Moss Proc. Natl. Acad. Sci. 89, 628–672]. Studies in mice have shown that the homolog of VCP in cowpox virus (CPV), referred to as the inflammation modulatory protein (IMP) can, in a mouse model, significantly diminish the specific footpad swelling response [C. G. Miller, S. N. Shchelkunov, and G. J. Kotwal Virol. 229, 126–133]. To determine the precise cellular changes at the site of infection, BALB/c mice were subcutaneously injected (in the backs) with CPV or a recombinant virus lacking IMP, CPV-IMP. Differences in histology were observed by staining the adjoining skin tissue sections with hematoxylin & eosin or by removal of the connective tissue and staining with May-Grunwald-Geimsa. All mice that were injected with the CPV-IMP experienced severe tissue destruction and formation of nodular lesions compared with the mice injected with CPV. Microscopic examination indicated significantly greater cellular infiltration and destruction of skeletal muscle cells in the sections of connective tissue and adjoining skin tissue, respectively, of the mice injected with the CPV-IMP [G. J. Kotwal et al. Mol. Cell. Biochem. in press]. Thus IMP preserves the tissue at the site of infection (viral habitat). In this review, we present evidence for molecular mimicry and evolutionary relationship to other homologs of IMP and discuss their relationships with other IMPs such as the poxviral chemokine and cytokine receptor-like proteins. J. Leukoc. Biol. 64: 68–71; 1998.
Antinociceptive effect of the calcium-binding protein MRP-14 and the role played by neutrophils on the control of inflammatory pain
Authors: Giorgi R , Pagano R L , Dias M A Amorim , Aguiar-Passeti T , Sorg C , Mariano M
Published: January 2018

Macrophages secrete a variety of chemical mediators that play a central role in the pathophysiology of inflammatory pain. Therefore, the activation or deactivation of these cells in an inflammatory focus could modulate the intensity of the algogenic response. Based on these premises and on our previous demonstration that the calcium-binding protein MRP-14, highly expressed in neutrophils, deactivates activated macrophages in vitro, we decided to investigate the role of MRP-14 and of neutrophils in the control of inflammatory pain in mice. Our results show that this protein is endowed with antinociceptive activity. When tested in the writhing model it was able to inhibit pain response but did not change the behavior of the animals in the hot plate test. This observation indicates that MRP-14 down-regulates inflammatory but not central pain. Using a model of acute neutrophilic peritonitis induced by glycogen, a close correlation between neutrophil migration and antinociception was detected. Surgical adrenalectomy demonstrated that the antinociceptive response induced by glycogen was not due to endogenous liberation of glucocorticoids. The treatment of animals either with a monoclonal antibody anti-MRP-14 or a monoclonal antibody that depletes the animals of neutrophils reverts the antinociceptive response observed in the glycogen-induced peritonitis. These data define the calcium-binding protein MRP-14 as a novel mediator for the control of inflammatory pain and consequently discloses an anti-inflammatory role for the neutrophil. J. Leukoc. Biol. 64: 214–220; 1998.
Expression of mRNA encoding neurotrophins and neurotrophin receptors in human granulocytes and bone marrow cells—enhanced neurotrophin-4 expression induced by LTB4
Authors: Laurenzi Maria Assunta , Beccari Tommaso , Stenke Leif , Sjölinder Mikael , Stinchi Sofia , Lindgren Jan Åke
Published: January 2018

The expression of neurotrophin and neurotrophin receptor mRNAs in human granulocytes and bone marrow cells was examined using ribonuclease protection assay and reverse transcription-polymerase chain reaction. The granulocytes expressed mRNA coding for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-4 (NT-4), but not neurotrophin-3 (NT-3). Moreover, the inflammatory mediator leukotriene B4 (LTB4) up-regulated the expression of NT-4 mRNA in granulocytes, but did not affect the expression of other neurotrophin mRNAs. Granulocytes generally lacked expression of mRNA coding for neurotrophin receptors. In contrast, human bone marrow cells consistently expressed mRNA for trkB (the BDNF and NT-4 receptor) and displayed variable expression of mRNA coding for trkA (the tyrosine kinase NGF receptor) and LNGFR (the low-affinity NGF receptor), whereas mRNA for trkC (the NT-3 receptor) was not expressed. Contrary to granulocytes, normal bone marrow cells generally expressed only low levels of mRNA encoding BDNF and NT-4. Expression of mRNA encoding NGF and NT-3 was not detected. However, significantly increased expression of BDNF mRNA was observed when bone marrow cells from patients with chronic myeloproliferative disorders (MPD) were analyzed. The results suggest that neurotrophins may act as granulocyte-derived effector molecules and that human bone marrow cells may be targets for these compounds, in particular BDNF and NT-4. J. Leukoc. Biol. 64: 228–234; 1998.
Characterization of cytokine differential induction of STAT complexes in primary human T and NK cells
Authors: Yu Cheng-Rong , Young Howard A , Ortaldo John R
Published: January 2018

Cytokines, IL-2, IL-4, IL-6, IL-7, IL-12, and IL-15 are key regulators of human peripheral blood T and NK cell activation and differentiation but the precise mechanisms that give rise to their differential activities within these cells are not clear. Recent studies reveal that a family of transcription factors, signal transducers and activators of transcription (STATs) directly mediate many cytokine signals. We analyzed the activation of STATs in primary human T and NK cells by a variety of specific cytokines. We demonstrate that IL-12 induces STAT4 only in freshly isolated primary NK cells, but not in primary T cells, consistent with the lack of the IL-12 receptor in resting T cells. In contrast, IL-4 induces different Cε GAS DNA-protein binding complexes in both T and NK cells. Moreover, IL-4 costimulation with IL-2 or IL-12 does not alter their own preferential GAS-like DNA binding patterns when Cε-, FcγRI-, and SIE GAS motif containing oligonucleotide probes are compared, suggesting that induction of GAS-like DNA-protein binding complexes by IL-2, IL-4, and IL-12 is highly selective and represents one important factor in determining specific gene activation. In addition, IL-6 and IL-2 synergistically induce homo- and heterodimerized STAT1α and STAT3 in both NK and T cells, consistent with their reported synergism in modulating perforin gene expression. We further demonstrated that IL-2, -7, and -15 induce multiple STAT proteins, including STAT5a, STAT5b, STAT1α, STAT3, and another unidentified FcγRI GAS DNA-binding protein. Finally, we observed that activated STAT5a and STAT5b proteins form distinct FcyRI GAS binding patterns in T and NK cells, suggesting that they might have different roles in gene regulation. Our data provide evidence that the differential responses in gene expression and cell activation seen in primary NK and T cells on direct stimulation with different cytokines may be a direct result of distinct activation of STAT transcription factors. J. Leukoc. Biol. 64: 245–258; 1998.
Modulation of P2X7 nucleotide receptor expression by pro- and anti-inflammatory stimuli in THP-1 monocytes
Authors: Humphreys Benjamin D , Dubyak George R
Published: January 2018

Regulation of P2X7 receptor expression is of interest because activation of this receptor by extracellular ATP triggers maturation and release of the proinflammatory cytokine interleukin-1β (IL-1β) in monocytes and macrophages. We report that interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α) synergistically induce P2X7R mRNA and functional responses in the human THP-1 monocytic cell line. Induction was dose dependent, with maximal functional activity requiring 1000 units/mL IFN-γ and 10 ng/mL TNF-α and incubations of 36–72 h. The up-regulation of P2X7R function by lipopolysaccharide (LPS)/IFN-γ and TNF-α/IFN-γ was markedly attenuated by coincubation with prostaglandin E2 or the cell permeant cyclic AMP analog dibutyryl cAMP (Bt2cAMP). Bt2cAMP did not significantly alter P2X7 function in HEK-293 cells stably transfected with the human P2X7 cDNA, indicating that Bt2cAMP does not exert a generalized effect on P2X7R synthesis or downstream signal transduction. These studies demonstrate that elevated cAMP negatively modulates P2X7R expression. J. Leukoc. Biol. 64: 265–273; 1998.
Tumor-induced immune dysfunction: the macrophage connection
Authors: Elgert Klaus D , Alleva David G , Mullins David W
Published: January 2018

Although macrophages (Mφs) mediate tumor cytotoxicity, display tumor-associated antigens, and stimulate antitumor lymphocytes, cancer cells routinely circumvent these host-mediated immune activities, rendering the host incapable of mounting a successful antitumor immune response. Evidence supporting a direct causal relationship between cancer and immune dysfunction suggests that the presence of neoplastic tissue leads to immunologic degeneration. Furthermore, substantial data demonstrate that tumor growth adversely alters Mφ function and phenotype. Thus, although Mφs can serve as both positive and negative mediators of the immune system, the importance of Mφs in tumor-induced immune suppression remains controversial. This review focuses on the evidence that tumor-derived molecules redirect Mφ activities to promote tumor development. Tumors produce cytokines, growth factors, chemotactic molecules, and proteases that influence Mφ functions. Many tumor-derived molecules, such as IL-4, IL-6, IL-10, MDF, TGF-β1, PGE2, and M-CSF, deactivate or suppress the cytotoxic activity of activated Mφs. Evidence that tumor-derived molecules modulate Mφ cytotoxicity and induce Mφ suppressor activity is presented. This information further suggests that Mφs in different in vivo compartments may be differentially regulated by tumor-derived molecules, which may deactivate tumor-proximal (in situ) Mφ populations while concurrently activating tumordistal Mφs, imparting a twofold insult to the host’s antitumor immune response. J. Leukoc. Biol. 64: 275–290; 1998.
Spontaneous and Fas-mediated apoptosis are diminished in umbilical cord blood neutrophils compared with adult neutrophils
Authors: Allgaier Bernhard , Shi Min , Luo DeFang , Koenig Joyce M
Published: January 2018

Apoptosis mediates neutrophil (PMN) phagocytosis and is influenced by cytokines and the Fas/Fas ligand pathway. To determine whether apoptosis of cord blood PMN differs from those of adults, cultured PMN were evaluated by morphological analysis, flow cytometry (TUNEL assay), and DNA gel electrophoresis. In addition, we studied the effect of anti-Fas IgM or cycloheximide on induction of PMN apoptosis. Spontaneous apoptosis (24 h) was less in cord blood PMN (mean ± SD; 29 ± 9 vs. adults, 56 ± 14%, P < 0.001). Treatment (6 h) with anti-Fas IgM induced less apoptosis in cord blood PMN (24 ± 6 vs. adults, 63 ± 7%, P < 0.001), as did treatment with cycloheximide (13 ± 10 vs. adults, 55 ± 16%, P < 0.01). These data suggest the pre-existence of proteins that inhibit apoptosis or the absence of those that promote apoptosis in cord blood PMN. J. Leukoc. Biol. 64: 331–336; 1998.
Activation of rat macrophages by Betafectin PGG-glucan requires cross-linking of membrane receptors distinct from complement receptor three (CR3)
Authors: Michalek Michael , Melican David , Brunke-Reese Deborah , Langevin Matthew , Lemerise Kristen , Galbraith William , Patchen Myra , Mackin William
Published: January 2018

PGG-glucan (Betafectin ) is a soluble, highly purified yeast (1,3)-β-glucan with broad anti-infective and immunomodulatory activities. These studies evaluated the ability of PGG-glucan to directly elicit O2– and tumor necrosis factor α (TNF-α) production by rat leukocytes in vitro. Particulate β-glucan stimulated O2– production by the rat NR8383 alveolar macrophage cell line and resident rat peritoneal macrophages, but soluble PGG-glucan did not. In contrast, presentation of PGG-glucan to cells after covalent immobilization to a plastic surface caused a direct stimulation of O2– and TNF-α production. The O2– response of rat leukocytes to immobilized PGG-glucan was inhibited by soluble PGG-glucan, indicating that cellular responses to both immobilized and soluble PGG-glucan occur via common cell surface receptors. Because complement receptor type three (CR3) has been proposed as a β-glucan receptor on human leukocytes, NR8383 cells were evaluated for the presence of CR3. Indirect immunofluorescence and flow cytometric analysis showed that despite being responsive to both particulate and immobilized β-glucans, NR8383 cells expressed no detectable CR3. These results indicate that the β-glucan receptors on NR8383 cells are not CR3 and suggest that physical presentation plays an important role in inducing proinflammatory leukocyte responses to PGG-glucan. J. Leukoc. Biol. 64: 337–344; 1998.
Lipopolysaccharide-stimulated TNF-α release from cultured rat Kupffer cells: sequence of intracellular signaling pathways
Authors: Lichtman Steven N , Wang Jian , Lemasters John J
Published: January 2018

We recently hypothesized that lipopolysaccharide (LPS) stimulation of rat Kupffer cells to induce tumor necrosis factor α (TNF-α) release requires internalization of LPS, acidification of endosomes, elevation of intracellular calcium, protein kinase C (PKC) activation, and protein tyrosine kinase (PTK) activation. This study uses inhibitors in pulse-chase experiments to determine the sequence of events of intracellular signals required for LPS-stimulated TNF-α release from Kupffer cells. Inhibitors of internalization (cytochalasin B, monodansylcadaverine) prevented LPS-stimulated TNF-α release when added simultaneously with LPS but when added 10 min after LPS, no significant inhibition occurred. The inhibitor of PTK, tyrphostin AG, blocked TNF-α release by only 39 ± 4% (P < 0.001 compared with TNF-α release when added simultaneously with LPS) when added 10 min after LPS. Inhibitors of endosomal acidification (bafilomycin A, monensin) inhibited LPS-stimulated TNF-α release by 92 ± 11% (P < 0.001 when no inhibitor was used) when added 10 min after LPS and their effect was totally abrogated when added 45 min after LPS. The PKC inhibitor, H-7, blocked TNF-α release by 94 ± 9% (P < 0.001 when no inhibitor was used) when added 30 min after LPS. The calcium channel blocker, nisoldipine, still inhibited LPS-stimulated TNF-α release when added 45 min after LPS. These data support the hypothesis that for LPS-stimulated TNF-α release in Kupffer cells, LPS must first be internalized, which may stimulate PTK activation. An intermediate step of signaling involves endosomal acidification. Elevation of intracellular calcium and PKC activation occur as late intracellular signaling events. J. Leukoc. Biol. 64: 368–372; 1998.
Contribution of the CXC chemokines IP-10 and Mig to the antitumor effects of IL-12
Authors: Kanegane Chiharu , Sgadari Cecilia , Kanegane Hirokazu , Teruya-Feldstein Julie , Yao Lei , Gupta Ghanshyam , Farber Joshua M , Liao Fang , Liu Li , Tosato Giovanna
Published: January 2018

The mechanisms by which interleukin-12 (IL-12) exerts antitumor effects have been difficult to dissect. In this study, we examined the potential contribution of the chemokines interferonγ-inducible protein-10 (IP-10) and Mig to the antitumor effects of IL-12. Using an athymic mouse model, local inoculations with IL-12 consistently produced tumor size reductions associated with characteristic tumor necrosis and vascular damage. These effects were indistinguishable from those produced by IP-10 or Mig injected locally in the same tumor model. Local and systemic treatment with IL-12 was associated with expression of the interferon-γ (IFN-γ), IP-10, and Mig genes and proteins in the tumor. Levels of IP-10 and Mig expression in the tumor, the liver, and the kidney were inversely correlated with tumor size. Administration in vivo of neutralizing antibodies to IP-10 and Mig reduced substantially the antitumor effects of IL-12 inoculated locally into the tumors. These results support the notion that IP-10 and Mig contribute to the antitumor effects of IL-12 through their inhibitory effects on tumor vasculature. J. Leukoc. Biol. 64: 384–392; 1998.
Leukocyte trafficking in experimental autoimmune uveitis in vivo
Authors: Parnaby-Price Adrian , Stanford Miles R , Biggerstaff John , Howe Lucy , Whiston Roy A , Marshall John , Wallace Graham R
Published: January 2018

Leukocyte trafficking from blood into tissue is a fundamental process in immune surveillance and the immune response to stimuli. Experimental autoimmune uveitis (EAU) is an animal model for posterior uveitis and is mediated by T lymphocytes and macrophages that infiltrate the posterior segment of the eye. To analyze leukocyte migration into retinal tissue during the course of EAU, labeled cells were identified in vivo by scanning laser ophthalmoscopy and in retinal flat-mounts by confocal microscopy. Adhesion of blood leukocytes to retinal endothelial cells in vivo was significantly raised 48 h before the appearance of clinical disease, and this correlated with the increased expression of CD54 on retinal vessels. Mitogen-activated spleen cells and CD4+ T cells only entered into retinal tissue in animals with clinical disease and not naive recipients. The disease status of the donor animal had no effect on leukocyte trafficking. These results, which identify leukocyte-endothelial cell interactions in vivo, suggest that the activation of the retinal endothelium is a prerequisite to leukocyte adhesion and extravasation into ocular tissue during EAU. J. Leukoc. Biol. 64: 434–440; 1998.
Genetic and immunological parameters governing in vivo susceptibility/resistance to retrovirally induced murine malignant histiocytosis
Authors: Panoskaltsis-Mortari Angela , Egeler R Maarten , Yaeger Thomas M , Yoneji Sumiko , Schmitz Laura , Lilly Frank , Nesbit Mark E , Blazar Bruce R
Published: January 2018

Malignant histiocytosis sarcoma virus (MHSV) arose as a recombinant of c-Harvey-ras murine sarcoma virus (Ha-MuSV) and Friend mink cell focus-forming virus (F-MCFV). It is a defective acute transforming retrovirus that, along with Friend murine leukemia helper virus (F-MuLV), induces malignant histiocytosis (MH) in susceptible adult mice. We have assessed the in vivo susceptibility to MHSV in inbred homozygous, F1 hybrid, congenic, and recombinant inbred (RI) mice. We have shown that: (1) in vivo resistance to MHSV is multigenic, regulated by MHC and non-MHC genes in a different fashion than with F-MCFV, F-MuLV, or Ha-MuSV; (2) using BXD RI mice, the resistance phenotype is linked with 95.8% probability to two linked loci, Pmv-9 and Iapls3-14, on chromosome 13 (homologous to the area of human chromosome 5 for which a chromosomal break point at position 5q35 is associated with human MH); and (3) CD4+ T cells are critical for MHSV resistance. J. Leukoc. Biol. 64: 441–450; 1998.
Ionizing radiation potentiates the induction of nitric oxide synthase by IFN-γ and/or LPS in murine macrophage cell lines: role of TNF-α
Authors: McKinney Leslie C , Aquilla Elizabeth M , Coffin Deborah , Wink David A , Vodovotz Yoram
Published: January 2018

Macrophages are activated to become cytotoxic by a highly coordinated set of cytokine signals. Ionizing radiation can mimic cytokine signals and lead to enhanced states of activation. We tested the ability of γ-radiation, alone and with interferon-γ (IFN-γ) and/or lipopolysaccharide (LPS), to induce nitric oxide (NO) production in J774.1 and RAW264.7 murine macrophages. NO was induced weakly, moderately, or strongly by IFN-γ alone, LPS alone, or IFN-γ + LPS, respectively. Radiation alone (0.5–50 Gy) did not induce NO, but enhanced NO production in a dose-dependent manner (0.5–5 Gy) when cells were exposed to IFN-γ or LPS 24 h post-irradiation. Immunoblots showed parallel induction of nitric oxide synthase (NOS2). Application of antitumor necrosis factor α (TNF-α) antibody before irradiation blocked induction of NO by IFN-γ. We conclude (1) that irradiated cells produce more NO in response to either IFN-γ or LPS and (2) that the increase is mediated by induction of TNF-α. J. Leukoc. Biol. 64: 459–466; 1998.
Monocyte-derived dendritic cells have a phenotype comparable to that of dermal dendritic cells and display ultrastructural granules distinct from Birbeck granules
Authors: Grassi Fernanda , Dezutter-Dambuyant Colette , McIlroy Dorian , Jacquet Christelle , Yoneda Kozo , Imamura Sadao , Boumsell Laurence , Schmitt Daniel , Autran Brigitte , Debre Patrice , Hosmalin Anne
Published: January 2018

Most monocyte-derived dendritic cells (DC) display CD1a, like Langerhans cells (LC) and some dermal DC, but their relationship with these skin DC remains unclear. To address this issue, we studied the expression of different antigens characteristic of skin DC and of monocyte/macrophages in CD1a+ and CD1a– monocyte-derived DC. Their phenotype indicated that they may be related to dermal DC rather than to LC, i.e., they were all CD11b-positive, and 72% were Factor XIIIa-positive, but they did not express E-cadherin nor VLA-6. It is interesting that CD1a+ and CD1a– cells showed intracytoplasmic granules that were different from LC Birbeck granules. These pheno-typical and ultrastructural features are comparable to those of CD14-derived DC obtained from cord blood precursors [C. Caux et al. J. Exp. Med. 184, 695–706]. These results show a close relationship between these two in vitro models, which are both related to dermal DC. J. Leukoc. Biol. 64: 484–493; 1998.
The role of IL-5 in bleomycin-induced pulmonary fibrosis
Authors: Gharaee-Kermani Mehrnaz , McGarry Bridget , Lukacs Nicholas , Huffnagle Gary , Egan Robert W , Phan Sem H
Published: January 2018

Eosinophils are known to express cytokines capable of promoting fibrosis. Interleukin-5 (IL-5) is important in regulating eosinophilopoiesis, eosinophil recruitment and activation. Lung IL-5 expression is elevated in pulmonary fibrosis, wherein the eosinophil is a primary source of fibrogenic cytokines. To determine the role of IL-5 in pulmonary fibrosis, the effects of anti-IL-5 antibody were investigated in a model of bleomycin-induced pulmonary fibrosis. Fibrosis was induced in mice by endotracheal bleomycin treatment. Animals were also treated with either anti-IL-5 antibody or control IgG. Lungs were then analyzed for fibrosis, eosinophil influx, chemotactic activity, and cytokine expression. The results show that a primary chemotactic activity at the height of eosinophil recruitment is IL-5. Furthermore, anti-IL-5 antibody caused significant reduction in lung eosinophilia, cytokine expression, and fibrosis. These findings taken together suggest an important role for IL-5 in pulmonary fibrosis via its ability to regulate eosinophilic inflammation, and thus eosinophil-dependent fibrogenic cytokine production. J. Leukoc. Biol. 64: 657–666; 1998.
β1 Integrin-dependent binding of Jurkat cells to fibronectin is regulated by a serine-threonine phosphatase
Authors: Seminario Maria-Cristina , Sterbinsky Sherry A , Bochner Bruce S
Published: January 2018

We investigated the effects of signaling molecule inhibitors on the expression and function of β1 integrins in Jurkat cells. Jurkat cells expressed α4β1 and α5β1, with significant levels of constitutively activated β1 integrins as assessed by labeling with mAb 15/7 that distinguishes between activation states. Adhesion to fibronectin (Fn) was mediated equally through α4 and α5 subunits, and was potentiated by the β1 integrin activating mAb 8A2. Fn adhesion was decreased by okadaic acid through effects on both α4β1 and α5β1. Tyrphostin A23 also decreased adhesion but was less potent. Neither inhibitor had any effect on the surface expression of total or activated β1 integrins. The effect of tyrphostin was completely reversed by 8A2; the effect of okadaic acid was only partially reversed. Using Calyculin A, we determined that Jurkat adhesion to Fn was regulated via protein phosphatase 1, independent of the levels of integrins or integrin activation epitopes. Activation of Jurkat cells with a CD3-stimulating mAb enhanced adhesion to Fn and was partially blocked by okadaic acid. These data demonstrate different regulatory pathways for constitutive versus activation-dependent adhesion via β1 integrins, and implicate both tyrosine kinases and serine-threonine phosphatases in integrin function. J. Leukoc. Biol. 64: 753–758; 1998.
The metamorphosis of a molecule: from soluble enzyme to the leukocyte receptor CD38
Authors: Ferrero Enza , Malavasi Fabio
Published: January 2018

Human CD38 is a 45-kDa type II membrane glycoprotein with an intricate pattern of expression in leukocytes, although evidence is accumulating of its quite widespread expression in cells of nonvascular origin. CD38 is a member of a nascent eukaryotic gene family encoding cytosolic and membrane-bound enzymes whose substrate is NAD, a coenzyme ubiquitously distributed in nature. Functionally, CD38 is an eclectic molecule with the ability not only to catalyze but also to signal, to mobilize calcium, and to adhere to itself, to hyaluronan, and to other ligands. Interaction with CD38 on various leukocyte subpopulations has profound though diverse consequences on their life-span, but these effects seem to be independent of the enzymatic activity of the molecule. CD38 challenges our expectations of a surface molecule and we must sift through its many guises to unmask its true nature. J. Leukoc. Biol. 65: 151–161; 1999.
Macrophages interact with enriched populations of distinct T lymphocyte subsets for the induction of severe destructive Lyme arthritis
Authors: DuChateau Brian K , Munson Erik L , England Douglas M , Lovrich Steven D , Callister Steven M , Jensen Jani R , Schell Ronald F
Published: January 2018

Severe destructive Lyme arthritis was detected in the hind paws of hamsters infused with enriched populations of either CD4+ or CD4- T lymphocytes along with macrophages exposed in vitro to formalin-inactivated Borrelia burgdorferi and then infected with the Lyme spirochete. Swelling was detected 4 days after infection, increased rapidly, peaked on day 8 of infection, and gradually decreased. Similarly, severe destructive arthritis was induced in hamsters infused with enriched populations of unfractionated T lymphocytes and macrophages exposed to spirochetes after infection with B. burgdorferi. Histopathological examination affirmed that hamsters infused with CD4+, CD4-, or unfractionated T lymphocytes and macrophages exposed to B. burgdorferi-induced arthritis. In addition, macrophages exposed in vitro to B. burgdorferi demonstrated both conventional and coiling phagocytosis, suggesting a mechanism by which CD4+ and CD4- T lymphocytes induce arthritis, respectively. These findings demonstrate that both CD4+ and CD4- subpopulations of T lymphocytes are capable of interacting with macrophages for the induction of severe destructive Lyme arthritis. J. Leukoc. Biol. 65: 162–170; 1999.
Chemokine-induced phosphorylation of CC chemokine receptor 5 (CCR5)
Authors: Olbrich Heike , Proudfoot Amanda E I , Oppermann Martin
Published: January 2018

The CC-chemokine receptor 5 (CCR5) mediates activation of T lymphocytes and macrophages by chemokines and is a major co-receptor for macrophage-tropic HIV-1 strains. Recently, it was shown that the natural CCR5 ligands RANTES, macrophage inflammatory protein-1á (MIP-1á), MIP-1β, and amino-terminal modifications of RANTES (Met-RANTES, AOP-RANTES) significantly differ in their abilities to induce sequestration of CCR5 from cellular surfaces. It was hypothesized that these findings may account for the observed differences between these molecules to inhibit HIV infectivity in vitro. Herein we review our work on early regulatory mechanisms that are initiated by ligand binding to CCR5 and that, conceptually, are involved in receptor endocytosis. A better understanding of these mechanisms may provide new therapeutic strategies to prevent HIV infection. J. Leukoc. Biol. 65: 281–285; 1999.
Inhibition of IL-4-inducible gene expression in human monocytes by type I and type II interferons
Authors: Dickensheets Harold L , Donnelly Raymond P
Published: January 2018

The Th2-type cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13), induce expression of a distinct subset of genes in human monocytes, including Fc∊RIIb (CD23), 15-lipoxygenase, IL-1 receptor antagonist (IL-1ra), and type I and type II IL-1 receptors (IL-1R). Type I interferons (IFN-α and IFN-β) and type Ii interferon (IFN-γ) inhibit induction of these genes by IL-4 and IL-13. However, the mechanism by which IFNs mediate this inhibition has not been defined. In this overview, we discuss the role of the transcription factor, STAT6 (signal transducer and activator of transcription-6) in mediating IL-4- and IL-13-induced gene expression in monocytes. We also discuss our recent findings that type I and type II IFNs suppress IL-4/IL-13-inducible gene expression by inhibiting tyrosine phosphorylation and nuclear translocation of STAT6. The ability of type I and type II IFNs to inhibit IL-4/IL-13-induced STAT6 activity is dose-and time-dependent, and is not unique to monocytes because IFNs induce the same effects in fibroblasts. Inhibition of STAT6 activity is not evident unless cells are preincubated with IFN for at least 1 h before IL-4 stimulation. Furthermore, inhibition can be blocked by actinomycin D, indicating a requirement for de novo transcription. We propose a model in which stimulation of monocytes by IFN activates de novo synthesis of an inhibitory factor, possibly one or more members of the SOCS/SSI/CIS gene family, capable of suppressing activation of STAT6 by IL-4 and IL-13. Because STAT6 activation plays an essential role in IL-4/IL-13-induced gene expression, the ability of IFN-β and IFN-γ to inhibit STAT6 activity provides an explanation for how IFNs can suppress IL-4/IL-13-inducible gene expression. J. Leukoc. Biol. 65: 307–312; 1999.
Sphingosine 1-phosphate: a prototype of a new class of second messengers
Authors: Spiegel Sarah
Published: January 2018

Sphingosine 1-phosphate (SPP) is an important sphingolipid-derived second messenger in mammalian cells that acts to promote proliferation and to inhibit apoptosis. Various growth factors increase the intracellular concentration of SPP by activating sphingosine kinase, the molecular cloning of which has revealed that it defines a new type of lipid kinase. Cell fate is influenced by the balance between the intracellular concentration of SPP and that of ceramide, a pro-apoptotic sphingolipid metabolite. The observation that a similar “rheostat” is a determinant of cell survival in yeast cells exposed to heat shock indicates that it is an evolutionarily conserved mechanism of stress regulation. SPP also acts extracellularly to inhibit cell motility and to influence cell morphology, effects that appear to be mediated by the G protein-coupled receptor EDG1. These observations indicate that SPP is the prototype of a new class of lipid mediators that exert both intracellular and extracellular actions. J. Leukoc. Biol. 65: 341–344; 1999.
Insights into the neurodegenerative process of Alzheimer's disease: a role for mononuclear phagocyte-associated inflammation and neurotoxicity
Authors: Cotter Robin L , Burke William J , Thomas Vince S , Potter Jane F , Zheng Jialin , Gendelman Howard E
Published: January 2018

Since the first description of Alzheimer's disease (AD) in 1907, significant progress was made into understanding disease pathophysiology. The enormous effort in AD research has translated into the discovery of genetic linkages for disease, into elucidating the structure and function of the etiologic β-amyloid protein, and into unraveling the seemingly complex neuroimmunological cascade that affects neuronal dysfunction. Although effective therapies do not currently exist, many are being developed. We propose that the neuropathogenesis of AD, in measure, revolves around the immunological activation of glial cells, which in turn leads to alterations in inflammatory neurotoxin production, and ultimately to neuronal injury and death. Elucidating the mechanisms involved in such glial cell immune activation should provide valuable insights into understanding the disease process and in providing effective therapeutics to prevent and/or retard the devastating neurodegeneration that afflicts so many of our elderly. J. Leukoc. Biol. 65: 416–427; 1999.
HIV-1-induced neuronal injury in the developing brain
Authors: Epstein Leon G , Gelbard Harris A
Published: January 2018

HIV-1 infection of the nervous system causes neuronal injury and death, resulting in cognitive, motor, and behavioral dysfunction in both adults and children. In infants a characteristic feature of HIV-1 infection is impaired brain growth resulting in secondary microcephaly with onset between 2 and 4 months of age. This post-natal period of brain development is particularly vulnerable to excitotoxic neuronal injury due to the active synaptogenesis and pruning that takes place at this age associated with over-expression of excitatory amino acid (EAA) receptors. HIV-1 infection of brain microglia and perivascular macrophages results in chronic inflammation manifest pathologically as diffuse microglial activation and reactive astrogliosis. Several inflammatory products of activated microglia, including tumor necrosis factor a (TNF-α) and platelet-activating factor (PAF) have been shown to act as neuronal toxins. This toxic effect can be antagonized by blocking NMDA (or AMPA) glutamate receptors, suggesting that (weak) excitotoxicity leads to oxidative stress, neuronal injury, and apoptosis. HIV-1 infection and chronic inflammation may also contribute disruption of the blood–brain barrier and could result in further entry into the CNS of toxic viral or cellular products or additional HIV-1-infected cells. We hypothesize that prolonged microglial activation during HIV-1 infection underlies the neuronal injury and impaired brain growth in affected infants. Further investigation of the interaction between HIV-1- infected/activated microglia and developing neurons seems warranted. The current understanding of HIV neuropathogenesis implies that therapeutic strategies should target the sustained immune activation in microglia, attempt to repair the integrity of the blood-brain barrier, and provide “neuroprotection” from excitotoxic neuronal injury. J. Leukoc. Biol. 65: 453–457; 1999.
Heterologous desensitization of IL-8-mediated chemotaxis in human neutrophils by a cell-binding fragment of fibronectin
Authors: Stanton Kimberly J , Frewin Mary Beth , Gudewicz Paul W
Published: January 2018

In this study, we have explored the mechanism for the desensitization of IL-8-mediated neutrophil chemotaxis by a cell-binding fragment of fibronectin (120-kDa FN). Preincubation of neutrophil suspensions with the 120-kDa FN fragment resulted in a heterologous desensitization of IL-8-mediated chemotaxis while not affecting neutrophil chemotaxis to either fMLP or zymosan-activated serum. Preincubation of neutrophils with the βx-integrin-activating antibody (TS2/16) mimicked the effects of the 120-kDa FN fragment while preincubating neutrophils with the β1-integrin blocking antibody (mAb13) abrogated the inhibitory effects of the 120-kDa FN fragment on IL-8-mediated chemotaxis. Furthermore, we also demonstrated that the 120-kDa FN fragment did not inhibit chemotaxis to the CXC chemokine MGSA/GROα which interacts with high affinity to the IL-8 receptor B (CXCR2). By in vivo phosphorylation of neutrophils and probing lysates with an anti-CXCR1 antibody, we demonstrated that the addition of the cell-binding fragment of fibronectin resulted in a time-dependent phosphorylation of CXCR1. These findings suggest that the mechanism of heterologous desensitization of IL-8-mediated chemotaxis following ligation of FN-dependent integrins is the result of phosphorylation of the CXCR1 receptor. J. Leukoc. Biol. 65: 515–522; 1999.
Dendritic cell differentiation pathways of CD34+ cells from the peripheral blood of head and neck cancer patients
Authors: Lathers Deanne M R , Lubbers Eve , Wright Mark A , Young M Rita I
Published: January 2018

Patients with head and neck squamous cell carcinoma (HNSCC) have increased levels of immune-suppressive peripheral blood CD34+ cells. This study showed that the peripheral blood CD34+ cells of HNSCC patients are capable of differentiating into dendritic cells. Because CD34+ cells can differentiate through several pathways into dendritic cell subpopulations, the intermediate cells through which the blood CD34+ cells of HNSCC patients differentiate were identified. After 6–7 days of culturing the CD34+ cells of HNSCC patients with granulocyte-macrophage colony-stimulating factor, stem cell factor, and tumor necrosis factor α, there appeared CD14+CD1a+ and a lesser proportion of CD14−CD1a+ cells resembling the precursor cells of the bipotential and committed dendritic cell differentiation pathways that have been described for cord blood CD34+ cells. To functionally analyze whether these populations were in fact precursor cells, they were isolated and cultured for an additional 10–12 days. Each of these populations was shown to function as precursor cells because they were able to develop into cells that resembled dendritic cells, al though a higher proportion developed from the CD14−CD1a+ cells. In contrast, expression of the dendritic activation/maturation marker CD83 was highest on the cells that developed from CD14+CD1a+ cells. Thus, the CD34+ cells whose levels are increased in HNSCC patients can develop into both committed and bipotential dendritic precursor cells, which can subsequently give rise to dendritic cells. J. Leukoc. Biol. 65: 623–628; 1999.
Superantigens augment antigen-specific Th1 responses by inducing IL-12 production in macrophages
Authors: Bright John J , Xin Zhicheng , Sriram Subramaniam
Published: January 2018

Superantigens (SAg) are microbial proteins that mediate antigen-presenting cell (APC)-T cell interaction by cross-linking MHC class II molecules with subsets of TcRVβ. SAgs are implicated in the pathogenesis of several infectious, inflammatory, and autoimmune diseases. In this study, we examined the influence of SEB on interleukin-12 (IL-12) production and the activation of antigen-specific Th1 responses. Addition of SEB augmented the antigen-induced proliferation of HS-17, a murine MBPp91-103 peptide-specific TcRVβ6+ CD4+ Th1 clone. SEB augments HS-17 T cell proliferation through its interaction with IAs molecules on macrophages, but not with the TcRVβ6 on HS-17 cells. On binding to IAs, SEB induces IL-12 production in macrophages, which in turn augments antigen-induced proliferation of HS-17 T cells. Treatment with anti-IAs mAb 10-3.6 inhibited the antigen- and SEB-induced IL-12 production and T cell proliferation. These results suggest that SAgs augment antigen-specific T cell responses by inducing IL-12 production in macrophages. J. Leukoc. Biol. 65: 665–670; 1999.
Monocyte CD14: a multifunctional receptor engaged in apoptosis from both sides
Authors: Heidenreich Stefan
Published: January 2018

Like all other immune system cells, monocytes and macrophages may undergo apoptotic cell death in response to specific triggers and mediators or as a consequence of aging. However, factors inducing apoptosis and the involved cellular and molecular mechanisms are much better investigated and understood for lymphocytes. Th2 cell-derived cytokines such as interleukin-4 (IL-4) are able to induce monocyte apoptosis most effectively. This process is preceded by down-regulation of the CD14 surface receptor. Mediators such as lipopolysaccharide (LPS) suppress and postpone apoptosis in parallel with up-regulation of CD14. Macrophages are rather resistant against apoptotic damage, and factors able to evoke apoptosis in monocytes are often ineffective in macrophages. Resistance of macrophages against apoptotic triggers may be beneficial for inflammatory processes where macrophages are engaged and needed as phagocytes for ingestion and removal of moribund cells. The multifunctional CD14 receptor of monocytes/macrophages is supposed to be involved in the apoptotic network on both sides: as a surface molecule of monocytes that can promote survival and antagonize apoptosis and as a recognition receptor of macrophages that enables or supports interaction with apoptotic cells. J. Leukoc. Biol. 65: 737–743; 1999.
The synthetic non-toxic drug 2,3-dimethyl-6(2-dimethylaminoethyl)-6H-indolo-(2,3-b)quinoxaline inhibits neutrophil production of reactive oxygen species
Authors: Harbecke Olle , Dahlgren Claes , Bergman Jan , Möller Lennart
Published: January 2018

The effects of the non-toxic drug 2,3-dimethyl-6(2-dimethylaminoethyl)-6H-indolo-(2,3-b)quinoxaline (B220) on the generation of reactive oxygen species from human neutrophils were investigated. The data show that B220 inhibits neutrophil release of reactive oxygen species, as well as intracellular generation of reactive oxygen species. The inhibition is not achieved through direct oxygen radical scavenger activity of B220, and the drug has no immediate effects on the activity of the assembled oxidase. Radical production and release were inhibited by all agonists tested [i.e. the protein kinase C-activating phorbol ester phobol myristate acetate; the receptor-specific agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP); and serum-opsonized yeast particles] in the presence of B220. The drug also inhibits phagocytosis and fMLP-induced mobilization of granules. However, based on the fact that the effects of B220 on phagocytosis and granule mobilization are much less significant than its effect on radical production, we suggest that the signal(s) affected by B220 is (are) located mainly downstream of the point at which the signals are generated to promote oxidase activation and phagocytosis or granule secretion, respectively. J. Leukoc. Biol. 65: 771–777; 1999.
Identification of CD137 as a potent monocyte survival factor
Authors: Langstein Joachim , Schwarz Herbert
Published: January 2018

CD137 (ILA/4-1BB), a member of the tumor necrosis factor (TNF) receptor family, promotes adherence and prolongs survival of human peripheral monocytes. It induces a strong expression of macrophage colony-stimulating factor (M-CSF), an essential monocyte survival factor. Monocyte survival induced by CD137 is primarily mediated by M-CSF and to a lesser extent by granulocyte-macrophage colony-stimulating factor and IL-3. Survival and induction of M-CSF are mediated via reverse signaling through a CD137 ligand expressed constitutively by peripheral monocytes. J. Leukoc. Biol. 65: 829–833; 1999.
The role of chemokines in the regulation of dendritic cell trafficking
Authors: Sozzani Silvano , Allavena Paola , Vecchi Annunciata , Mantovan Alberto
Published: January 2018

The immunobiology of dendritic cells (DC) involves localization in tissues and trafficking via the lymph or blood to lymphoid organs. Appropriate assays representative of different steps of DC trafficking (e.g., reverse transmigration) provide the tools to dissect the migratory properties of these cells. Chemokines have emerged as important regulators of DC migration. DC are both the target and the source of chemokines. DC express receptors for and respond to a set of chemoattractants that overlap with, but are distinct from, those active on other leukocytes. Differential expression of the CCR6 receptor reveals heterogeneity among DC populations. Functional maturation is associated with loss of responsiveness to chemokines present at sites of inflammation and acquisition of a receptor repertoire that renders these cells responsive to signals that guide their localization in lymphoid organs. A better understanding of the molecular basis of DC trafficking may provide molecular and conceptual tools to direct and modulate DC traffic as a strategy to up-regulate and orient specific immunity. J. Leukoc. Biol. 66: 1–9; 1999.