bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemokine synthesis in the HSV-1-infected cornea and its suppression by interleukin-10
Authors: Tumpey Terrence M , Cheng Hao , Yan Xiao-Tian , Oakes John E , Lausch Robert N
Published: January 2018

Herpes simplex virus type 1 (HSV-1) infection of the murine cornea results in a tissue-destructive inflammatory response. In this study we show that virus infection induces the synthesis of macrophage inflammatory protein-2 (MIP-2), MIP-1α, and monocyte chemoattractant protein-1 (MCP-1). However, only the production of MIP-2 and MIP-1α coincided with the influx of leukocytes into the cornea. IL-10 treatment markedly suppressed chemokine message and protein synthesis in vivo. Local administration of IL-10 also dramatically reduced the number of T cells and neutrophils migrating into the cornea and suppressed the severity of corneal disease. The inflammatory response could also be suppressed by the passive transfer of neutralizing antibody to MIP-1α but not MCP-1. We conclude that local IL-10 administration can suppress chemokine synthesis, thereby ameliorating corneal disease. Furthermore, our results indicate that MIP-1α plays a major role in herpes stromal keratitis development, whereas MCP-1 does not.
Melanocortin peptides inhibit production of proinflammatory cytokines and nitric oxide by activated microglia
Authors: Delgado René , Carlin Andrea , Airaghi Lorena , Demitri Maria Teresa , Meda Lucia , Galimberti Daniela , Baron Pierluigi , Lipton James M , Catania Anna
Published: January 2018

Inflammatory processes contribute to neurodegenerative disease, stroke, encephalitis, and other central nervous system (CNS) disorders. Activated microglia are a source of cytokines and other inflammatory agents within the CNS and it is therefore important to control glial function in order to preserve neural cells. Melanocortin peptides are pro-opiomelanocortin-derived amino acid sequences that include α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH). These peptides have potent and broad anti-inflammatory effects. We tested effects of α-MSH (1-13), α-MSH (11-13), and ACTH (1-24) on production of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) in a cultured murine microglial cell line (N9) stimulated with lipopolysaccharide (LPS) plus interferon γ (IFN-γ). Melanocortin peptides inhibited production of these cytokines and NO in a concentration-related fashion, probably by increasing intracellular cAMP. When stimulated with LPS + IFN-γ, microglia increased release of α-MSH. Production of TNF-α, IL-6, and NO was greater in activated microglia after immunoneutralization of endogenous α-MSH. The results suggest that α-MSH is an autocrine factor in microglia. Because melanocortin peptides inhibit production of proinflammatory mediators by activated microglia they might be useful in treatment of inflammatory/degenerative brain disorders.
Adoptive immunotherapy of cancer using monocyte-derived macrophages: rationale, current status, and perspectives
Authors: Andreesen Reinhard , Hennemann Burkhard , Krause Stefan W
Published: January 2018

Adoptive transfer of host defense cells may be able to correct an otherwise defective generation of competent immune cells in patients with cancer. Ex vivo-grown cytotoxic macrophages (MAC) able to recognize and destroy tumor cells but not normal cells are effective in murine models of metastasizing tumors. After the development of large-scale technology to generate MAC in vitro from blood monocytes (MO), clinical trials in cancer patients have proven the feasibility and safety of infusing >3 × 109 autologous MO-derived MAC activated by interferon-γ or lipopolysaccharide. Various modalities of adoptive immunotherapy with human MAC have been realized: routes of application used were intravenous, intraperitoneal, intrapleural, and through selective hepatic artery perfusion. In addition, MAC have been generated from MO collected after granulyte-macrophage colony-stimulating factor treatment in vivo. Biodistribution studies using 111indium-labeled cells have revealed localization of MAC to sites of bulk tumor growth on regional infusion as well as to liver metastases on systemic application. Malignant ascites disappeared in about 50% of patients after intraperitoneal treatment, yet no other evidence of therapeutic efficacy of MAC could be demonstrated. Further advances of adoptive transfer of MO-derived cells are developed with emphasis on the generation of antigen-presenting cells primed in vitro with tumor cells or specific peptides. J. Leukoc. Biol. 64: 419–426; 1998.
The identification and characterization of umbilical cord blood-derived human basophils
Authors: Kepley Christopher L , Pfeiffer Janet R , Schwartz Lawrence B , Wilson Bridget S , Oliver Janet M
Published: January 2018

Cross-linking allergen-specific immunoglobin E on human peripheral blood basophils results in the release of histamine and other inflammatory mediators that initiate allergy and asthma. The signaling pathways leading from IgE binding to mediator release have not been well established, mainly due to the difficulty in obtaining adequate numbers of highly purified basophils. It was the goal of this study to easily obtain FcεRI-positive human basophils in high yield and purity for studies of signal transduction pathways. We describe an in vitro culture system in which pulsing normal human cord blood leukocytes with interleukin-3 (IL-3) for 3–4 h followed by incubation in medium with fetal bovine serum generates a cell population that is predominately FcεRI positive between 14 and 28 days of culture. These cells resemble peripheral blood basophils when examined by light and electron microscopy. Like normal blood basophils, they express the integrins, CD11b, CD18, CD29, and CD49d. A majority of the IL-3-pulsed cells also express a marker recognized by the basophil-specific antibody, 2D7. FceRI cross-linking results in a time and dose-dependent release of histamine. FcεRI cross-linking also stimulates protein-tyrosine phosphorylation, thought to be the first event leading to the IgE-mediated activation of peripheral blood basophils. These studies establish cord blood as an accessible source from which basophil-like cells can be developed to examine FcεRI-mediated signal transduction. J. Leukoc. Biol. 64: 474–483; 1998.
Impact of aging on innate immunity
Authors: Pawelec Graham , Solana Rafael , Remarque Ed , Mariani Erminia
Published: January 2018

Immune responses in higher organisms are triggered by the recognition of a limited diversity of microbiological products by cells of the innate or “natural” immune system. As a result, in addition to the direct protective effect of natural immunity, antigen-presenting cells, particularly dendritic cells, are activated to process and present an enormous number of peptide antigens to the T lymphocytes of the adaptive immune system. These, together with the B lymphocytes, then mediate specific immune responses and maintain acquired immunological memory. The aging immune system is less well able to cope with infectious disease than the youthful immune system; this review will briefly consider what is known of the age-associated alterations in innate immunity, and how these may also impact on adaptive immunity. J. Leukoc. Biol. 64: 703–712; 1998.
ISCOMs: an adjuvant with multiple functions
Authors: Sjölander Anders , Cox John C , Barr Ian G
Published: January 2018

Aluminum salts are currently the only widely used adjuvant for human vaccines. Over the past 10–15 years, a large research effort has attempted to find novel adjuvants with ability to induce abroad range of immune responses, including cell-mediated immunity. The immunostimulating complex or ISCOM is one adjuvant with multiple adjuvant properties. ISCOMs are open cage-like complexes typically with a diameter of about 40 nm that are built up by cholesterol, lipid, immunogen, and saponins from the bark of the tree Quillaia saponaria Molina. ISCOMs have been demonstrated to promote antibody responses and induce T helper cell as well as cytotoxic T lymphocyte responses in a variety of experimental animal models, and have now progressed to phase I and II human trials. This review describes recent developments in the understanding of the structure, composition, and preparation of ISCOMs and will cover important aspects of the understanding of the adjuvant functions of ISCOMs and how they act on the immune system. J. Leukoc. Biol. 64: 713–723; 1998.
Nordihydroguaiaretic acid blocks secretory and endocytic pathways in human dendritic cells
Authors: Ramoner Reinhold , Rieser Claudia , Bartsch Georg , Thurnher Martin
Published: January 2018

Nordihydroguaiaretic acid (NDGA), an antioxidant and inhibitor of the lipoxygenase arm of the arachidonic acid metabolism, was recently demonstrated to inhibit transport of secretory proteins to the Golgi complex. We have investigated the effects of NDGA on the secretory and endocytic activity of cultured human blood dendritic cells (DC). Treatment with NDGA strongly diminished cytokine secretion by DC. Moreover, NDGA reduced in a dose- and time-dependent fashion fluid phase as well as receptor-mediated endocytosis in DC. Zileuton and MK-886, specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein, respectively, had no effect. Likewise, N-acetyl-l-cysteine, a thiol antioxidant precursor of glutathione, did not affect DC function. Finally, serum remarkably protected the cells from the inhibitory effects of NDGA. Our data demonstrate that NDGA not only disrupts vesicular transport along the secretory route but is also a potent inhibitor of the endocytic pathways in human DC and that NDGA has inhibitory properties different from those described. J. Leukoc. Biol. 64: 747–752; 1998.
During human thymic development, β1 integrins regulate adhesion, motility, and the outcome of RHAMM/hyaluronan engagement
Authors: Gares Sheryl L , Giannakopoulos Nadia , MacNeil Donna , Faull Randall J , Pilarski Linda M
Published: January 2018

During human thymic differentiation, interactions between fibronectin (Fn)/β1 integrins and hyaluronan (HA)/RHAMM control motility and Fn/β1 integrins mediate spontaneous Fn-dependent adhesion. Multinegative (MN, CD3–4–8–) thymocytes exhibit strong spontaneous adherence to Fn (75%) that was efficiently inhibited by anti-α5β1 and only weakly inhibited by anti-α4β1. The relatively weak adherence of unfractionated thymocytes to Fn required both α4β1 and α5β1. Video time-lapse microscopy indicates that a subset of thymocytes also undergo spontaneous Fn-dependent motility mediated by α5β1, α4β1, and the HA-receptor RHAMM, but not by CD44. The loss of motility after hyaluronidase treatment of thymocytes indicated that motility is strongly dependent on HA. Of motile cells, 55% were DP, 19% were DN, and 24% were CD4+SP, but only 1% were CD8+SP. Overall, for MN thymocytes, β1 integrin mediated Fn-adhesion, but after expression of CD4/CD8, β1 integrins mediated Fn-dependent motility. Treatment with the activating anti-β1 mAb QE.2E5 inhibited thymic motility and converted otherwise nonadherent thymocytes to an adherent state. High-avidity interactions via integrins appear to supercede the motogenicity of RHAMM and HA, suggesting that integrin avidity may regulate RHAMM. During thymic development, changes in adhesion or motility appear to be mediated by integrin avidity modulation. J. Leukoc. Biol. 64: 781–790; 1998.
Separation of integrin-dependent adhesion from morphological changes based on differential PLC specificities
Authors: Wooten David K , Teague T Kent , McIntyre Bradley W
Published: January 2018

In normal lymphocytes an inside-out signal up-regulating integrin adhesion is followed by a ligand-mediated outside-in cell spreading signal. Protein kinase C (PKC) inhibition blocks lymphocyte adherence to and spreading on fibronectin. In contrast, putative PLC inhibitors yield distinct differences with respect to adhesion and morphology. The phosphatidylinositol-specific phospholipase C (PLC) inhibitor neomycin blocked spreading of CD3/CD28-activated T cells on fibronectin by disrupting adhesion. Furthermore, when an additional inside-out signal for fibronectin adhesion is unnecessary such as with HPB-ALL T leukemic or phorbol-myristate-acetate-treated normal T cells, neomycin treatment does not alter adhesion or morphology. However, the phosphatidylcholine-specific PLC inhibitor D609 abrogates cell spreading without affecting adhesion to fibronectin in these cells as well as the CD3/CD28-activated T cells. These results strongly suggest that inside-out signaling for the integrin α4β1 in lymphocytes proceeds through phosphatidylinositol-specific PLC and PKC, whereas the outside-in signal utilizes phosphatidylcholine-specific PLC and PKC. J. Leukoc. Biol. 65: 127–136; 1999.
Regulation of early peritoneal neutrophil migration by macrophage inflammatory protein-2 and mast cells in experimental peritonitis
Authors: Mercer-Jones Mark A , Shrotri Milind S , Heinzelmann Michael , Peyton James C , Cheadle William G
Published: January 2018

Neutrophil (PMN) migration into the peritoneal cavity in response to fecal peritonitis is an important mechanism of host defense against bacterial invasion. We show that the murine C-X-C (PMN-specific) chemokine, macrophage inflammatory protein-2 (MIP-2), on intraperitoneal injection in mice, causes PMN migration into the peritoneum. MIP-2 mRNA and protein were expressed by peritoneal leukocytes after cecal ligation and puncture (CLP) in mice and neutralization of MIP-2 reduced peritoneal PMN migration. A prerequisite for neutrophil-endothelial adhesion and subsequent migration from the circulation is selectin-mediated rolling. Pretreatment of mice with an anti-P-selectin antibody before intraperitoneal injection of MIP-2 significantly reduced peritoneal PMN migration. However, there are no reports that a C-X-C chemokine can up-regulate endothelial selectins. We postulated that MIP-2, when injected intraperitoneally, interacts with a cell that is known to release factors that up-regulate endothelial selectins. A likely candidate is the mast cell, which contains histamine and tumor necrosis factor α (TNF-α), and both of these factors induce selectins. Intraperitoneally injected MIP-2 caused an early significant increase in peritoneal TNF-α, whereas histamine levels were unaffected. In a subsequent experiment, mast cell-deficient mice and their normal controls were then injected intraperitoneally with MIP-2 or underwent CLP. Significantly fewer PMNs migrated into the peritoneal cavity in the mast cell-deficient mice after MIP-2 injection or CLP. Thus, our findings indicate that mast cells and MIP-2 are necessary for PMN migration into the peritoneum in response to intra-abdominal infection, and that MIP-2 appears to facilitate this through an increase in TNF-α release. J. Leukoc. Biol. 65: 249–255; 1999.
Multiple roles for PI 3-kinase in the regulation of PLCγ activity and Ca2+ mobilization in antigen-stimulated mast cells
Authors: Barker Sheryll A , Lujan Don , Wilson Bridget S
Published: January 2018

Cross-linking the IgE-bound Fc∊RI with polyvalent antigen leads to Ca2+-dependent degranulation from mast cells and basophils, initiating the allergic response. This overview addresses novel roles for PI 3-kinase in the regulation of signaling events that lie downstream of Fc∊RI-mediated tyrosine kinase activation. The first novel role for PI 3-kinase is in the regulation of PLCγ activity and is demonstrated by a dramatic inhibition of Fc∊RI-induced Ins(1,4,5)P3 production after treatment of RBL-2H3 cells with wortmannin, a PI 3-kinase inhibitor. We show that PI 3-kinase lipid products support Ins(1,4,5)P3 production in at least two ways: by promoting translocation and phosphorylation of PLCγ1 and by direct stimulation of both PLCγ isoforms. In vitro stimulation of PLCγ activity by PtdIns(3,4,5)P3 synergizes with activation by in vivo tyrosine phosphorylation for maximal enzymatic activity. A second novel role for PI 3-kinase is in the regulation of antigen-stimulated Ca2+ influx. Compared with control cells, Ca2+ responses are markedly diminished in antigen-stimulated cells after wortmannin pretreatment. Differences include both a longer lag time to the initial elevation in Ca2+ after antigen and an inhibition of the sustained Ca2+ influx phase. However, thapsigargin challenge during the sustained phase demonstrates no difference in the state of the Ca2+ stores in antigen-stimulated cells in the presence or absence of wortmannin. These data suggest that sufficient Ins(1,4,5)P3 is synthesized in wortmannin-treated cells to mobilize intracellular calcium stores and, furthermore, that the affected phase of Ca2+ influx is unlikely to be attributed to capacitative mechanisms. These data are consistent with a model where at least two pathways mediate Ca2+ influx in antigen-stimulated RBL-2H3 cells, one that is dependent on signals from empty stores (capacitive influx) and another that is downstream of PI 3-kinase. J. Leukoc. Biol. 65: 321–329; 1999.
Signal transduction by reactive oxygen species in non-phagocytic cells
Authors: Finkel Toren
Published: January 2018

A growing body of evidence suggests a potential role for oxygen-derived radicals such as superoxide anions and hydrogen peroxide as intracellular signaling molecules. Recently, progress has been made regarding the regulation of oxidant production in non-phagocytic cells. Significant gaps in understanding persist, however, especially in regard to the source(s) of oxidant production and the direct intracellular target(s) of oxygen radicals. Nonetheless, numerous recent studies have implicated a dynamic change in the intracellular redox state as an important determinant in a host of cellular decisions ranging from growth, to apoptosis, to cellular senescence. J. Leukoc. Biol. 65: 337–340; 1999.
Involvement of JAK2, but not PI 3-kinase/Akt and MAP kinase pathways, in anti-apoptotic signals of GM-CSF in human eosinophils
Authors: Miike Satoshi , Nakao Atsuhito , Hiraguri Masaki , Kurasawa Kazuhiro , Saito Yasushi , Iwamoto Itsuo
Published: January 2018

Granulocyte-macrophage colony-stimulating factor (GM-CSF) transmits anti-apoptotic signals in eosinophils and is involved in tissue eosinophilia at the site of allergic inflammation. We determined whether phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinase (MAP kinase) are involved in anti-apoptotic signals of GM-CSF in eosinophils. GM-CSF phosphorylated Akt, a downstream component of PI 3-kinase, and MAP kinases (ERK1 and ERK2) at 10 min after stimulation in eosinophils. GM-CSF prevented eosinophil apoptosis and sustained its survival during the 5-day culture. However, neither two PI-3 kinase inhibitors, wortmannin and LY294002, nor MEK inhibitor PD98059 inhibited GM-CSF-induced survival of eosinophils, although wortmannin and PD98059 inhibited GM-CSF-induced Akt phosphorylation and MAP kinase activation in eosinophils, respectively. In contrast, JAK2 inhibitor AG-490 inhibited both GM-CSF-induced JAK2 phosphorylation and cell survival in eosinophils. These results indicate that activation of JAK2, but not activation of PI 3-kinase/Akt and MAP kinase pathways, is critical for anti-apoptotic signals of GM-CSF in human eosinophils. Our findings suggest that manipulation of JAK2 activation would be useful for the treatment of allergic disorders. J. Leukoc. Biol. 65: 700–706; 1999.
Regulation of delta opioid receptor expression by anti-CD3-ε, PMA, and ionomycin in murine splenocytes and T cells
Authors: Li Ming D , McAllen Kathy , Sharp Burt M
Published: January 2018

Previous studies have shown that low levels of delta opioid receptor (DOR) mRNA were detectable by reverse transcription polymerase chain reaction (RT-PCR) in unstimulated splenocytes from BALB/c female mice. This study demonstrates that DOR transcripts can be detected in freshly obtained splenocytes from CD1 female mice as well. The results of studies using quantitative competitive RT-PCR showed that DOR transcripts in splenic T cells increased from < 1 copy/cell to 22 and 42 copies/cell, respectively, after stimulation with anti-CD3-ε for 24 and 48 h compared to the level in freshly obtained T cells. In the presence of actinomycin D, anti-CD3-ε did not affect the rate of degradation of DOR mRNA, suggesting that its stability is not altered by anti-CD3-ε. After incubation with phorbol myristate acetate (PMA) and ionomycin, the expression of DOR mRNA in splenocytes and T cells was significantly reduced compared with unstimulated cells in culture. In addition, the inhibitory effect of PMA prevented anti-CD3-ε-stimulated DOR expression. These data suggest that signaling through the T cell receptor complex by anti-CD3-ε regulates DOR expression differently than PMA and ionomycin. J. Leukoc. Biol. 65: 707–714; 1999.
TRANCE is a TNF family member that regulates dendritic cell and osteoclast function
Authors: Wong Brian R , Josien Regis , Choi Yongwon
Published: January 2018

Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) is a new member of the TNF family emerging as a key regulator of the immune system and of bone development and homeostasis. TRANCE is expressed on activated T cells and activates mature dendritic cells (DC), suggesting that it plays a role in the T cell-DC interaction during an immune response. Furthermore, TRANCE is expressed on osteoblasts stimulated with vitamin D3, dexamethasone, and parathyroid hormone. TRANCE, when expressed on osteoblasts, induces osteoclastogenesis and osteoclast activation, suggesting that it links known calciotropic hormones to bone resorption. TRANCE mediates its effects via the TRANCE-receptor (TRANCE-R/RANK), whereas its activity can be inhibited by the soluble decoy receptor osteoprotegerin/osteoclast inhibitory factor (OPG/OCIF). OPG can be neutralized by another TNF-family member, the TNF-related apoptosis-inducing ligand (TRAIL), suggesting that TRANCE is part of a complex cytokine network that regulates a diverse set of functions. We will discuss the current literature describing TRANCE and its receptors and its role in controlling DC and osteoclast function. J. Leukoc. Biol. 65: 715–724; 1999.
Role of CD8α+ and CD8α− dendritic cells in the induction of primary immune responses in vivo
Authors: Maldonado-López Roberto , De Smedt Thibaut , Pajak Bernard , Heirman Carlo , Thielemans Kris , Leo Oberdan , Urbain Jacques , Maliszewski Charlie R , Moser Muriel
Published: January 2018

Data from adoptive transfer of mature dendritic cells (DC) indicate that they are responsible for the induction of primary immunity. Two subclasses of DC have been recently identified in spleen that differ in their phenotype and in certain regulatory features. In vitro, both subsets have the capacity to activate naive T cells, although CD8α+ DC have been shown to induce T cell apoptosis and to stimulate lower levels of cytokines compared with CD8α− DC. The objective of this study was to analyze the function of these distinct DC types in vivo. Our results show that both subsets, pulsed extracorporeally with antigen and injected in the footpads of syngeneic mice, sensitize an antigen-specific T cell primary response. However, CD8α+ cells trigger the development of Th1-type cells, whereas CD8α− DC induce a Th2-type response. These observations suggest that the Th1/Th2 balance in vivo is regulated by the antigen-presenting-cells of the primary immune responses. J. Leukoc. Biol. 66: 242–246; 1999.
Activation and interaction of CD44 and hyaluronan in immunological systems
Authors: Siegelman Mark H , DeGrendele Heather C , Estess Pila
Published: January 2018

Adhesive interactions between receptors on vascular endothelial cells (EC) and circulating leukocytes are pivotal in regulating leukocyte extravasation. Although primary adhesion of lymphocytes to EC has been primarily attributed to the selectin family of receptors, CD44 can also mediate this function when activated to bind its ligand hyaluronan (HA). Triggering through the T cell receptor induces activated CD44 and CD44-dependent primary adhesion in both human and mouse lymphocytes, and the interaction can mediate the extravasation of activated T cells into an inflamed site. Lymphocytes capable of CD44/HA-dependent primary adhesion are found in peripheral blood of some rheumatologic patients, and their presence is associated with concurrent symptomatic or active disease. Thus, circulating T cells bearing activated CD44 may represent a pathogenically important subpopulation of activated cells that is elevated under conditions of chronic inflammation. Together, these data add to the selectin and immunoglobulin gene families a new receptor/ligand pair and further our understanding of their potential physiological role; i.e., antigen-specific T cell activation together with local vascular inflammation permits the CD44/HA interaction and subsequent T cell extravasation. J. Leukoc. Biol. 66: 315–321; 1999.
Tumor's other immune targets: dendritic cells
Authors: Esche Clemens , Lokshin Anna , Shurin Galina V , Gastman Brian R , Rabinowich Hannah , Watkins Simon C , Lotze Michael T , Shurin Michael R
Published: January 2018

The induction of apoptosis in T cells is one of several mechanisms by which tumors escape immune recognition. We have investigated whether tumors induce apoptosis in dendritic cells (DC) by co-culture of murine or human DC with different tumor cell lines for 4–48 h. Analysis of DC morphological features, JAM assay, TUNEL, caspase-3-like and transglutaminase activity, Annexin V binding, and DNA fragmentation assays revealed a time- and dose-dependent induction of apoptosis in DC by tumor-derived factors. This finding is both effector and target specific. The mechanism of tumor-induced DC apoptosis involved regulation of Bcl-2 and Bax expression. Double staining of both murine and human tumor tissues confirmed that tumor-associated DC undergo apoptotic death in vivo. DC isolated from tumor tissue showed significantly higher levels of apoptosis as determined by TUNEL assay when compared with DC isolated from spleen. These findings demonstrate that tumors induce apoptosis in DC and suggest a new mechanism of tumor escape from immune recognition. DC protection from apoptosis will lead to improvement of DC-based immunotherapies for cancer and other immune diseases. J. Leukoc. Biol. 66: 336–344; 1999.
Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states
Authors: Yang Xiao-Dong , Corvalan Jose R F , Wang Ping , Roy Catherine M-N , Davis C Geoffrey
Published: January 2018

Interleukin-8 (IL-8) is a potent chemotactic cytokine implicated in the pathogenesis of a number of inflammatory disease states. Agents that block the binding of IL-8 to its receptor have been shown to block inflammation in animal models of disease. This suggests that drugs specifically targeting IL-8 may prove efficacious in treating multiple human diseases. To this end, we developed a panel of fully human anti-IL-8 monoclonal antibodies (mAbs). These human antibodies were generated from XenoMouse™ strains, mice created by introducing megabase-size unrearranged human immunoglobulin heavy and κ light chain loci into a mouse genome in which the corresponding endogenous loci have been inactivated. From the panel of more than 50 mAbs, two antibodies, K4.3 and K2.2, were further characterized and evaluated for their specificity, productivity, affinity, and biological activity. Both K4.3 and K2.2 bind human IL-8 with high affinity (Kd of K4.3 = 2.1 × 10−10 M; Kd of K2.2 = 2.5 × 10−10 M). In vitro, in addition to blocking IL-8 binding to human neutrophils, K4.3 and K2.2 blocked a number of IL-8-dependent cellular functions including neutrophil activation, up-regulation of the cell adhesion receptor CD11b/ CD18, and neutrophil chemotaxis, suggesting that the fully human anti-IL-8 mAbs derived from XenoMouse strains are potent anti-inflammatory agents. This was further supported by in vivo studies in which K4.3 and K2.2 significantly inhibited IL-8-induced skin inflammation in rabbits. A pharmacokinetic study in Cynomolgus monkeys demonstrated that the α phase half-life is 9.4 h and the β phase 10.9 days, typical of human mAbs in monkeys. These data support advancing a fully human anti-IL-8 mAb into clinical trials to treat inflammatory diseases. J. Leukoc. Biol. 66: 401–410; 1999.`
Reactivity of monoclonal antibodies EG1 and EG2 with eosinophils and their granule proteins
Authors: Nakajima Hirokazu , Loegering David A , Kita Hirohito , Kephart Gail M , Gleich Gerald J
Published: January 2018

Use of the murine monoclonal antibodies EG1 and EG2 has been based on the assumption that EG2 recognizes activated eosinophils. We examined the reactivity of EG1 and EG2 with eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and stimulated and nonstimulated eosinophils from normal donors. By radioimmunoassay, EG1 recognized only ECP, whereas EG2 recognized both ECP and EDN. By Western blot, EG1 reacted with ECP, EG2 reacted with both ECP and EDN, but EG2 could not distinguish between lysates of stimulated and nonstimulated eosinophils. By immunofluorescence, EG1 and EG2 at 20 μg/mL stained 95–100% of nonstimulated eosinophils, regardless of fixative; EG1 and EG2 at 0.1 μg/mL stained 61–90% of acetone- and paraformaldehyde-fixed and only 5–21% of methanol-fixed nonstimulated eosinophils. Thus, the reactivity of EG1 and EG2 with eosinophils depends on the method of fixation and antibody concentration; and EG2, in contrast to previous reports, cannot reliably discriminate between resting and activated eosinophils. J. Leukoc. Biol. 66: 447–454; 1999.
The macrophage in atherosclerosis: modulation of cell function by sterols
Authors: van Reyk David M , Jessup Wendy
Published: January 2018

Lipid-laden macrophage foam cells are an early and persistent component of atherosclerotic lesions. As such they are likely to play a key role in disease progression, both as scavengers of lipid and as inflammatory mediators. The sterol content of macrophage foam cells is largely native cholesterol together with a small but significant proportion of oxidized cholesterol (oxysterols). Few in vitro investigations of the influence of sterol accumulation on macrophage function have used cells that contain physiologically or even pathologically representative amounts of cholesterol or, more particularly, oxysterols. However, recent studies, using macrophages with a sterol content much closer to that of authentic foam cells, show that the presence of oxysterols causes an impairment in macrophage cholesterol export, suggesting a key role for oxysterols in the maintenance of the foam cell phenotype. The implications of physiologically relevant levels of oxysterols on a wider range of macrophage function remain to be investigated. J. Leukoc. Biol. 66: 557–561; 1999.
Macrophages—proliferation, activation, and cell cycle proteins
Authors: Vadiveloo Peter K
Published: January 2018

Our understanding of mammalian cell proliferation has increased enormously over the past decade. A major advance has been identification and characterization of cyclins and their catalytic partners, cyclin-dependent kinases (cdks). The following brief review highlights the role of macrophages as a cell model for many of the major advances in this field. Macrophages were central to the identification of D-type cyclins and cdk4. In addition, it appears the first work showing that cell cycle proteins are the targets for anti-proliferative agents was performed in macrophages. In these latter studies, and a number of subsequent studies in other cell types, it was shown that many anti-mitogenic agents repressed cyclin and/or cdk expression. However, recent work in this laboratory suggests macrophage D-type cyclins may also be involved in processes other than proliferation. We have unexpectedly found that macrophages treated with lipopolysaccharide (LPS) express high levels of cyclin D2, even though LPS simultaneously represses cyclin D1 levels and potently blocks proliferation. These data, and those showing the yeast extract Zymosan A also raises cyclin D2 levels, suggest cyclin D2 plays a role in macrophage activation. J. Leukoc. Biol. 66: 579–582; 1999.
Sialic acid binding receptors (siglecs) expressed by macrophages
Authors: Munday James , Floyd Helen , Crocker Paul R
Published: January 2018

Sialic acids are structurally and topographically well-suited to function as ligands in cellular recognition events. Sialoadhesin (Sn) is a sialic acid binding receptor uniquely expressed by macrophage subsets. It is a member of the immunoglobulin (Ig) superfamily with 17 extracellular domains. Sn is a prototypical member of the siglec family of sialic acid binding proteins, which includes CD22, myelin-associated glycoprotein, CD33, and siglec-5. These membrane proteins are involved in discrete functions in the hemopoietic, immune, and nervous systems. The sialic acid binding region of siglecs is localized within the membrane-distal, amino-terminal domain and in the case of Sn, it has been characterized in atomic detail by X-ray crystallography, nuclear magnetic resonance, and site-directed mutagenesis. Our studies on Sn indicate that this receptor is likely to function as a macrophage accessory molecule in a variety of cell-cell and cell-extracellular matrix interactions. CD33 and siglec-5 are also expressed on macrophage subsets as well as other myeloid cells. However, unlike Sn, the properties of these molecules indicate a predominant role in signaling functions rather than in cell-cell interactions. J. Leukoc. Biol. 66: 705–711; 1999.
Rottlerin, a PKC isozyme-selective inhibitor, affects signaling events and cytokine production in human monocytes
Authors: Kontny Ewa , Kurowska Mariola , Szczepańska Katarzyna , Maśliński Wodzimierz
Published: January 2018

The implication of select protein kinase C (PKC) isoenzymes in cytokine production by human monocytes was investigated using an isozyme-selective inhibitor of PKC, rottlerin. We found that lipopolysaccharide (LPS) triggers cytosol-to-membrane translocation of PKCα and δ isoenzymes, whereas phorbol ester (PMA) induces translocation of several PKC isoforms. Moreover, we show that in LPS- and PMA-stimulated monocytes rottlerin affects several cellular responses. (1) At low (15 μM) concentration it blocks translocation of PKCδ, diminishes DNA binding activity of AP-1 transcription factor, and attenuates cytokine production [tumor necrosis factor α (TNF-α) > interleukin-1β (IL-1β)]. (2) At high (50 μM) concentration it prevents translocation of PKCα, and subsequently inhibits ERK1/ERK2 phosphorylation, DNA binding activities of AP-1 and nuclear factor-κB transcription factors, and the production of both tested cytokines. Thus, we propose that cytosol-to-membrane translocation of PKCα and PKδ isoenzymes may represent early steps in the signaling cascades that lead to TNF-α and IL-1β production in human monocytes. J. Leukoc. Biol. 67: 249–258; 2000.
Human mast cell migration in response to members of the transforming growth factor-β family
Authors: Olsson Niclas , Piek Ester , ten Dijke Peter , Nilsson Gunnar
Published: January 2018

Mast cells are known to accumulate at sites of inflammation, however, the chemotaxins involved remain largely undefined. Transforming growth factor-β (TGF-β) isoforms regulate numerous cellular functions, including cell growth and differentiation, formation of extracellular matrix, and the immune response. In this study we have compared the potency of different members of the TGF-β family as human mast cell chemotaxins, and analyzed the expression of TGF-β binding proteins on human mast cells. We were able to demonstrate that the maximal chemotactic response was attained at approximately 40 fM for the three TGF-β isoforms, with TGF-β3 being more effective than TGF-β1 and TGF-β2 at this concentration. This effect was observed in both the HMC-1 human mast cell line and in cultured primary mast cells. In addition, TGF-β1, TGF-β2, and less efficiently, TGF-β3 inhibited the proliferation of HMC-1 cells. The migratory response is probably mediated through interaction with the TGF-β serine/threonine type I and II receptors that were found to be expressed on the cells. No expression of TGF-β type III receptor, endoglin, or the endothelial TGF-β type I receptor ALK-1 could be detected. These results provide evidence that TGF-β isoforms are highly potent chemotaxins for human mast cells and can play an important role in the recruitment of mast cells in inflammatory reactions. J. Leukoc. Biol. 67: 350–356; 2000.
Serum amyloid A is an activator of PMN antimicrobial functions: induction of degranulation, phagocytosis, and enhancement of anti-Candida activity
Authors: Badolato Raffaele , Wang Ji Ming , Stornello Sarah-Linnéa , Ponzi Alessandro Negro , Duse Marzia , Musso Tiziana
Published: January 2018

Serum amyloid A (SAA) is a 12-kDa protein secreted in large amounts by liver cells during microbial infections or inflammatory diseases. We have recently reported that SAA induces chemotaxis of polymorphonuclear cells (PMN), monocytes, and T lymphocytes and stimulates their adhesion to endothelial monolayers. In this study, we investigated whether SAA regulates PMN antimicrobial activities. We found that recombinant SAA (rSAA), at concentrations comparable to serum levels attained during an acute phase response, is a potent activator of PMN. Stimulation of PMN by rSAA results in a rapid and transient increase of cytosolic calcium concentration and up-regulation of cell-surface expression of antigens involved in adhesion and microbial recognition such as CD11c and CD16. In addition, stimulation of PMN with rSAA increases secretion of lactoferrin, an antimicrobial protein that is contained in specific granules of PMN and enhances PMN phagocytic activity against heat-killed Candida albicans. Finally, activation of PMN with rSAA enhances their anti-Candida activity within 30 min of stimulation. These results suggest that SAA is involved in up-regulating PMN antimicrobial activities and that high circulating concentrations of SAA as seen in the acute phase response may constitute a potential host defense mechanism against fungal infections. J. Leukoc. Biol. 67: 381–386; 2000.
Suppression of T cell function: a potential role for transcriptional repressor ICER
Authors: Bodor Josef , Bodorova Jana , Gress Ronald E
Published: January 2018

In this article, we review the inducible cAMP early repressor (ICER) and its possible critical involvement in modulation of T cell responsiveness by its capacity to transcriptionally attenuate interleukin-2 (IL-2) gene expression. It seems clear that the failure to produce the IL-2 is an important determinant of anergy induction. It is important that the CD28-responsive element (CD28RE), a composite DNA binding element consisting of NFAT and cyclic AMP-responsive (CRE)-like motifs in position of –160 of IL-2 promoter has the high affinity for ICER binding as well as NFAT/ICER complex formation. Moreover, CD28RE with adjacent DNA sequences was also shown to be essential for conferring anergy in T lymphocytes. Because ICER does not possess a transactivation domain required for the recruitment of CBP/p300, the binding of ICER to CD28RE and/or composite motifs containing CRE-like DNA motifs may lead to uncoupling of CBP/p300 thus extinguishing IL-2 expression as well as expression of numerous other cytokines and chemokines. J. Leukoc. Biol. 67: 774–779; 2000.
Bioavailability and metabolism of rosemary infusion polyphenols using Caco‐2 and HepG2 cell model systems
Authors: Achour Mariem , Saguem Saad , Sarriá Beatriz , Bravo Laura , Mateos Raquel
Published: January 2018

BACKGROUND

Rosmarinus officinalis is an aromatic plant used in folk medicine as a result of the therapeutic properties associated with its phenolic composition, being rich in rosmarinic acid (RA) and caffeic acid (CA). To better understand the bioactivity of these compounds, their absorption and metabolism were assessed in human Caco‐2 and HepG2 cells, as small intestine and liver models, respectively, using RA and CA standards, as well as a rosemary infusion and ferulic acid (FA).

RESULTS

Test compounds were partially up‐taken and metabolized by Caco‐2 and HepG2 cells, although a higher metabolization rate was observed after hepatic incubation compared to intestinal incubation. CA was the compound best absorbed followed by RA and FA, showing metabolites percentages of 30.4%, 11.8% and 4.4% in Caco‐2 and 34.3%, 10.3% and 3.2% in HepG2 cells, respectively. RA in the rosemary infusion showed improved bioavailability compared to pure RA. Methyl derivatives were the main metabolites detected for CA and RA after intestinal and hepatic metabolism, followed by methyl‐glucuronidates and glucuronidates. RA was also minimally hydrolyzed into CA, whereas FA only was glucuronidated. Rosemary polyphenols followed the same biotransformation pathways as the standards. In addition, phase II derivatives of luteolin were observed.

CONCLUSION

Rosemary polyphenols are partially metabolized in both the intestine and liver. © 2018 Society of Chemical Industry
Estimation of the liquid water content and Z–LWC relationship using Ka‐band cloud radar and a microwave radiometer
Authors: Oh Su‐Bin , Lee Yong Hee , Jeong Jong‐Hoon , Kim Yeon‐Hee , Joo Sangwon
Published: January 2018

Cloud microphysical variables are needed to evaluate and improve cloud parameterization and data assimilation in a numerical weather model. In order to obtain high spatiotemporal resolution data for the cloud, data from the Ka‐band cloud radar (KaCR), an instrument specialized for cloud observation, were used. In this study, the liquid water content (LWC) was estimated, and the reflectivity–liquid water content (Z–LWC) relationships were derived using the vertical profiles of radar reflectivity from the KaCR and the liquid water path (LWP) from a microwave radiometer. The data were collected at the Boseong National Center for Intensive Observation of Severe Weather in the Republic of Korea during an intensive observation period in 2014 (2014‐IOP, 16 June to 15 July 2014). First, the KaCR reflectivity was corrected using the linear depolarization ratio from the KaCR. The process also involved removing reflectivity profiles that have signal attenuation, compared with the cloud‐top heights retrieved from a satellite. The LWC profiles were calculated from the LWP by dividing using the weight of the KaCR reflectivity. Different constants were derived from the Z–LWC relationship according to each respective echo type. Therefore, the KaCR echoes were categorized into non‐precipitating clouds, precipitating clouds, and raindrops, using a micro rain radar and a ceilometer. The Z–LWC relationships were finally derived for each categorized echo. The results of this study suggest that the new method should be useful for retrieving cloud microphysical variables. These relationships allowed the estimation of 3D LWC in high resolution using a single KaCR platform.
Stability of essential spectra of singular Sturm‐Liouville differential operators under perturbations small at infinity
Authors: Sun Huaqing , Qi Jiangang
Published: January 2018

This paper is concerned with the stability of essential spectra of singular Sturm‐Liouville differential operators with complex‐valued coefficients. It is proved that the essential spectrum of the corresponding minimal operator is preserved by perturbations small at infinity with respect to the unperturbed operator. Based on it, 1‐dimensional Schrödinger operators under local dilative perturbations are studied.
Imaging macrophage distribution and density in mammary tumors and lung metastases using fluorine‐19 MRI cell tracking
Authors: Makela Ashley V. , Foster Paula J.
Published: January 2018

Purpose

The presence of tumor‐associated macrophages (TAMs) correlates with breast cancer progression and metastatic spread. Metastasis‐associated macrophages (MAMs) are also recruited to distant sites, where they support metastatic growth. In this study, we demonstrate that in vivo fluorine‐19 (19F)‐based MRI cell tracking can evaluate the density and distribution of macrophages within murine breast cancer tumors and associated metastases.

Methods

Three murine breast cancer cell lines with different metastatic potentials (4T1, 168FARN, and 67NR) were implanted into the mammary fat pad in mice. In vivo whole body 19F MRI was performed on tumor‐bearing mice 24 hours post‐intravenous injection of a perfluorocarbon (PFC) agent, which was taken up by macrophages in situ.

Results

TAMs were detected mainly in the periphery of primary tumors, and higher numbers of TAMs were detected in the more aggressive 4T1 tumors. Tumors had significantly greater 19F spins/mm3 when they were smaller, suggesting more TAM infiltration in early‐stage tumors. 19F signal was observed within lung metastases in mice with 4T1 tumors, and fluorescence microscopy confirmed the presence of PFC‐positive macrophages.

Conclusion

This study shows for the first time proof of the ability to use MRI cell tracking to visualize MAMs in the lungs. The ability to detect and monitor the number of TAMs in individual tumors with 19F MRI would allow for identification of breast tumors with heavy infiltration of TAMs and could be used as a biomarker for decisions about how to best treat these patients as well as for monitoring responses to therapy. Magn Reson Med 80:1138–1147, 2018. © 2018 International Society for Magnetic Resonance in Medicine.
From “Non‐encounters” to autonomic agency. Conceptions of patients with low back pain about their encounters in the health care system
Authors: Holopainen Riikka , Piirainen Arja , Heinonen Ari , Karppinen Jaro , O'Sullivan Peter
Published: January 2018

Low back pain is a considerable health problem which affects people around the world, causing major healthcare costs. The use of qualitative research methods enables us to describe and understand patients’ experience of, and attitudes to, healthcare. The aim of the present phenomenographic study was to identify and describe the contextual nature of the conceptions of patients with low back pain of their encounters in the HCS. Seventeen patients with chronic or episodic low back pain classified as “high risk” were interviewed in open recall interviews, using videos of patients’ initial physiotherapy sessions that had been recorded previously. The data were analysed using the phenomenographic method. Patients’ conceptions of their clinical journey were formulated by a variety of themes: convincing care, lifestyle change, participation, reciprocality and ethicality of encounters. The themes varied in four categories: “non‐encounters”, seeking support, empowering collaboration and autonomic agency. The results showed a range of clinical interactions – from very negative and disempowering, to empowering and life changing. The key differences between the first and second categories were professionals “being present” and patients starting to understand their low back pain. Between the second and third category, the key aspects were strong therapeutic alliance and the active participation of the patient. Finally, the key differences between the third and fourth categories were the patient being in charge and taking responsibility while knowing that help was available if required. The results may help in improving the care of patients with low back pain.
Generalized Kleinman‐Newton method
Authors: Geromel José C. , Deaecto Grace S.
Published: January 2018

This paper addresses the general problem of optimal linear control design subject to convex gain constraints. Classical approaches based exclusively on Riccati equations or linear matrix inequalities are unable to treat problems that incorporate feedback gain constraints, for instance, the reduced‐order (including static) output feedback control design. In this paper, these two approaches are put together to obtain a genuine generalization of the celebrated Kleinman‐Newton method. The convergence to a local minimum is monotone. We believe that other control design problems can be also considered by the adoption of the same ideas and algebraic manipulations. Several examples borrowed from the literature are solved for illustration and comparison.