bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of Nramp2 in activated mouse macrophages is dissociated from regulation of the Nramp1, classical inflammatory genes, and genes involved in iron metabolism
Authors: Wardrop S L , Wells C , Ravasi T , Hume D A , Richardson D R
Published: September 2022

Nramp2 is a widely expressed metal-ion transporter that is involved in dietary iron absorption in the duodenum and iron uptake from transferrin in peripheral tissues. Nramp1 is a related gene involved in regulation of host pathogen interaction. Nramp2 has at least two alternatively spliced isoforms, one of which contains an iron-responsive element in its 3′-untranslated region. In this study, we investigated the regulation of both isoforms of Nramp2 in activated primary macrophages from mouse strains with wild-type (Bcgr) or mutant (Bcgs) alleles. The Nramp2-IRE and/or -nonIRE transcripts were up-regulated in all mouse strains analyzed after treatment with interferon-γ and lipopolysaccharide. cDNA microarray analysis revealed that Nramp2 regulation is controlled discordantly from other iron-regulated genes and classical macrophage-activation genes in different mouse strains. We suggest that Nramp2 is regulated independently of known iron-responsive genes in macrophages, and its function in host defense is unrelated to Nramp1.
Role of chemokines in the biology of natural killer cells
Authors: Robertson Michael J
Published: September 2022

Natural killer (NK) cells participate in innate and adaptive immuneresponses to obligate intracellular pathogens and malignant tumors. Twomajor NK cell subsets have been identified in humans:CD56dim CD16+ and CD56bright CD16−. RestingCD56dim CD16+ NK cells express CXCR1, CXCR2, CXCR3, CXCR4,and CX3CR1 but no detectable levels of CC chemokine receptors on thecell surface. They migrate vigorously in response to CXCL12 and CXC3L1. In contrast, resting CD56bright CD16− NK cells expresslittle CXCR1, CXCR2, and CXC3R1 but high levels of CCR5 and CCR7. Chemotaxis of CD56bright CD16− NK cells is stimulated mostpotently by CCL19, CCL21, CXCL10, CXCL11, and CXCL12. Followingactivation, NK cells can migrate in response to additional CC and CXCchemokines. Cytolytic activity of NK cells is augmented by CCL2, CCL3,CCL4, CCL5, CCL10, and CXC3L1. Moreover, proliferation of CD56dim CD16+ NK cells is costimulated by CCL19 and CCL21. Activated NK cells produce XCL1, CCL1, CCL3, CCL4, CCL5, CCL22, and CXCL8. Chemokines secreted by NK cells may recruit other effector cellsduring immune responses. Furthermore, CCL3, CCL4, and CCL5 produced byNK cells can inhibit in vitro replication of HIV. CCL3 and CXL10expression appear to be required for protective NK cell responses invivo to murine cytomegalovirus or Leishmania major,respectively. Moreover, NK cells participate in the in vivo rejectionof transduced tumor cells that produce CCL19 or CCL21. Thus, chemokinesappear to play an important role in afferent and efferent NK cellresponses to infected and neoplastic cells.
Monocyte cell adhesion induced by a human aminoacyl-tRNA synthetase-associated factor, p43: identification of the related adhesion molecules and signal pathways
Authors: Park Heonyong , Park Sang Gyu , Lee Joong-Won , Kim Taeho , Kim Gyuyoup , Ko Young-Gyu , Kim Sunghoon
Published: September 2022

An aminoacyl-tRNA synthetase-associated factor, p43, was recently shown to be secreted to induce a proinflammatory response. Because a proinflammatory response involves the cell-cell adhesion between endothelial and immune cells, we first examined the mechanism of p43-induced cell-cell adhesion of myelomonocytic leukemia cells. Intercellular adhesion molecule-1 (ICAM-1) was up-regulated by p43 and mediated p43-induced cell-cell adhesion via the interaction with LFA-1 or Mac-1. We also investigated p43-stimulated signaling pathways involved in the homotypic THP-1 cell adhesion. Because the specific inhibitors for PI3-K (phosphatidylinositol 3-kinase), ERK (extracellular signal-regulating kinase), and p38 MAPK (mitogen-activated protein kinase) blocked p43-stimulated ICAM-1 expression and homotypic THP-1 cell adhesion, these kinases were responsible for p43-induced cell-cell adhesion. p43-Dependent activation of ERK was inhibited by PI3-K inhibitors, and the activation of p38 MAPK was not. Thus, the results of this work suggest that p43 should induce cell-cell adhesion via the PI3-K/ERK- and p38 MAPK-dependent up-regulation of ICAM-1.
Reversible phosphatidylserine expression on blood granulocytes related to membrane perturbation but not DNA strand breaks
Authors: Yang Ming-Yu , Chuang Hau , Chen Rong-Fu , Yang Kuender D
Published: September 2022

Exposure of phosphatidylserine (PS) on the outer leaflet of the cell membrane is recognized as an early indicator of programmed cell death (apoptosis) in plant and mammalian cells. Currently, there is no literature describing that PS expression on the surface of white blood cells is reversible. We found that a hypotonic 0.2% NaCl or NH4Cl lysing solution used to separate white blood cells from red blood cells induced a reversible PS expression on the cell surface of granulocytes and monocytes but not lymphocytes. This reversible PS expression was associated with change of plasma membrane potential but not degranulation-associated membrane mobilization or DNA fragmentation. In contrast, TNF-α induced an irreversible PS expression, associated with apoptotic DNA fragmentation shown on gel electrophoresis. The fact that hypotonic shock induced a reversible PS expression on granulocytes, and TNF-α induced an irreversible PS expression associated with apoptotic DNA fragmentation indicate the new insight that expression of PS on the outer cell surface does not always represent cell apoptosis. Also, the reversible PS expression was associated with altered plasma-membrane potential but not DNA strand breaks, indicating that early PS expression may be related to the membrane perturbation but not directly related to DNA fragmentation in certain types of cells.
Activation of phagocytic cell NADPH oxidase by norfloxacin: a potential mechanism to explain its bactericidal action
Authors: El Bekay Rajaa , Álvarez Moisés , Carballo Modesto , Martín-Nieto José , Monteseirín Javier , Pintado Elizabeth , Bedoya Francisco J , Sobrino Francisco
Published: September 2022

The mechanisms underlying the bactericidal power of fluoroquinolones against intracellular parasites in host macrophages remain poorly understood. We have analyzed the effect of norfloxacin, a fluoroquinolone antibiotic, on the production of reactive oxygen intermediates (O2•− and H2O2) and NADPH oxidase activity in mouse macrophages. The generation of anion superoxide (O2•−) was found to be significantly greater in macrophages incubated with norfloxacin than in untreated controls. This enhancing effect of norfloxacin was dose-dependent and reached maximal values within 10 min after its addition. The O2•− generated was mainly intracellular, as determined by the use of specific dyes, such as lucigenin and luminol, and able to diffuse freely through the cell membrane. Also, the production of H2O2 was increased in macrophages in response to norfloxacin. The positive effect of norfloxacin was associated to an enhanced mobilization of NADPH oxidase subunits p47phox and p67phox from the cytosol to the plasma membrane in phagocytic cells. The effect of the antibiotic persisted in vivo for several hours. These data support the notion that norfloxacin inhibits mycobacterial growth within phagocytic cells by enhancing intracellular production of O2•− and other reactive oxygen species.
Toll-like receptor 9 mediates CpG-DNA signaling
Authors: Chuang Tsung-Hsien , Lee Jongdae , Kline Lois , Mathison John C , Ulevitch Richard J
Published: September 2022

Among the bacterial products known to activate the innate immune ‘1system is bacterial DNA. This activity resides within the nonmethylated CpG motifs of the DNA and is recapitulated using appropriate synthetic CpG containing oligodeoxynucleotides (CpG-ODN). TLR9-deficient mice were shown to exhibit a nonresponsive phenotype-to-bacterial DNA and CpG-ODN. Here, we describe a model system to further characterize CpG-ODN and TLR9 interactions using ectopically expressed TLR9 in HEK293 cells. Expression of TLR9 confers cellular responsiveness to CpG-ODN but not to the other bacterial products. Previous studies identified species-specific CpG-containing sequences; here, we show that expression of murine TLR9 favors responses to CpG-ODN motifs specific to mouse cells, and expression of human TLR9 favors CpG-ODN known to preferentially activate human cells. Response patterns to various CpG-ODN motifs were parallel when cells containing an ectopically expressed TLR9 and endogenous receptor were compared. Here, we also show that TLR9 acts at the cell surface and engages an intracellular signaling pathway that includes MyD88, IRAK, and TRAF6.
Capacitative Ca2+ influx and activation of the neutrophil respiratory burst. Different regulation of plasma membrane- and granule-localized NADPH-oxidase
Authors: Granfeldt Daniel , Samuelsson Marie , Karlsson Anna
Published: September 2022

The neutrophil NADPH-oxidase may be activated in the plasma membrane, resulting in release of oxygen metabolites extracellularly, or in the granule or phagosomal membranes, giving intracellular production of oxidants. An increase in [Ca2+]i mediated through binding of fMLF to its receptor is part of a signaling cascade that activates the plasma membrane-localized oxidase. In contrast, a rise in [Ca2+]i induced by a Ca2+ ionophore results in activation of the intracellular pool of oxidase. We mimicked fMLF-induced emptying of intracellular Ca2+ stores with thapsigargin. This induced a pronounced intracellular oxidase activity but no extracellular release of oxidants. The thapsigargin-induced effect was dependent on capacitative Ca2+ influx, because the effect was inhibited dose-dependently by EGTA and the Ca2+ channel blocker La3+. At La3+ concentrations between 200 and 400 μM, thapsigargin also induced a massive extracellular production of superoxide anion. No other channel blockers tested induced a similar effect. We conclude that elevation in [Ca2+]i by capacitative Ca2+ influx induces NADPH-oxidase activation at an intracellular site. Further, activation of the plasma membrane-localized NADPH-oxidase is regulated by a more complex Ca2+ signaling, involving capacitative Ca2+ influx and possibly the specific action of La3+-sensitive Ca2+ channels.
Activation of macrophages by gliadin fragments: isolation and characterization of active peptide
Authors: Tučková Ludmila , Novotná Jana , Novák Petr , Flegelová Zuzana , Květoň Tomáš , Jelínková Lenka , Zídek Zdeněk , Man Petr , Tlaskalová-Hogenová Helena
Published: September 2022

Celiac disease, induced by dietary gluten, is characterized by mucosal atrophy and local inflammation associated with cell infiltration and activation. Unlike other food proteins, gluten and its proteolytic fragments, besides inducing a specific immune response, were shown to activate components of innate immunity and cause, e.g., direct stimulation of TNF-α and IL-10 and a significant rise in NO production by peritoneal macrophages. The identity of the active fragments was established by separating the peptic digest of gliadin by RP-HPLC chromatography. The purest fraction with the highest activity was analyzed by mass spectrometry, and the gliadin peptide sequence was identified as VSFQQPQQQYPSSQ. This peptide (T) and its N- and C-terminally shortened forms (A, B, C and D, E, F) were synthesized. Peptide B (FQQPQQQYPSSQ) elicited the highest TNF-α, IL-10, and RANTES secretion and increase in IFN-γ-primed NO production by mouse macrophages. In contrast, C-terminally shortened peptides had a lower ability to stimulate macrophages than the native form.
T cell-mediated signaling to vascular endothelium: induction of cytokines, chemokines, and tissue factor
Authors: Monaco Claudia , Andreakos Evangelos , Young Sylvia , Feldmann Marc , Paleolog Ewa
Published: September 2022

Adhesion of leukocytes to the vascular endothelium is an early event in inflammation. Since cell-cell signaling may be an important stimulus for endothelial activation, we focused in this study on the role of contact-mediated activation by T lymphocytes of endothelial cells (EC). T lymphocytes were cultured with anti-CD3 monoclonal antibody or in the presence of a combination of TNF-α, interleukin (IL)-6, and IL-2, prior to fixation and coculture with human umbilical vein EC. Fixed, activated (anti-CD3- or cytokine-stimulated), but not unstimulated T cells, induced release of monocyte chemotactic protein-1, IL-8, and IL-6 by EC in a contact-dependent manner. Moreover, expression of tissue-factor antigen and activity was also significantly increased. Addition of anti-CD40 ligand antibody abolished T cell-induced activation of EC. Our data suggest that contact-mediated activation of EC by T cells, involving ligand:counter ligand interactions such as CD40:CD40 ligand, may represent a novel pathogenic mechanism of progression in inflammatory diseases such as atherosclerosis or rheumatoid arthritis.
Endothelins regulate mediator production of rat tissue-cultured mucosal mast cells. Up-regulation of Th1 and inhibition of Th2 cytokines
Authors: Coulombe Martin , Battistini Bruno , Stankova Jana , Pouliot Philippe , Bissonnette Elyse Y
Published: September 2022

Mast cells have been shown to produce endothelin-1 (ET-1) and to express ET receptors. Thus, we postulated that ETs modulate mast cell mediator production in an autocrine manner. Rat tissue-cultured mast cells (RCMC-1) were incubated with exogenous ET-1 or ET-3, and β-hexosaminidase release and TNF, IL-4, IL-10, IL-12, IL-13, macrophage inflammatory protein-1α (MIP-1α), and nitric oxide (NO) production were investigated. ET-1 and -3 induced the release of β-hexosaminidase and TNF and of mRNA expression. An antagonist of the ETB receptor subtype abrogated ET-stimulated TNF release, although ETA and ETB receptors have been identified by immunocytochemistry. It is interesting that ET-1 and ET-3 inhibited (25–30%) mRNA expression of Th2-type cytokines (IL-4, IL-10, and IL-13) and increased IL-12 release (39% and 41%, respectively) without affecting MIP-1α and NO production. Thus, our data suggest that ETs may play an important role in modulating the cytokine network by regulating Th1/Th2 cytokine production by mast cells.
Flt-3 ligand (FL) drives differentiation of rat bone marrow-derived dendritic cells expressing OX62 and/or CD161 (NKR-P1)
Authors: Brissette-Storkus Cynthia S , Kettel J C , Whitham T F , Giezeman-Smits K M , Villa L A , Potter D M , Chambers William H
Published: September 2022

Bone marrow-derived dendritic cells (DC) of the rat have not been as well characterized as those from the mouse. Here, large quantities of bone marrow-derived rat DC were generated when Flt-3 ligand (FL) was used as an adjunct to granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4). These cells displayed a typical DC phenotype, expressing MHC class II, CD54, CD80, CD86, and CD11b/c. These DC also uniformly expressed low levels of CD161 and expressed OX62 in a bimodal distribution. Few cells were recovered from cultures grown without FL, and they failed to express OX62 or CD161. The DC generated with FL were more potent antigen-presenting cells in mixed lymphocyte cultures than cells grown without FL, and among FL-derived cells, the OX62+ cells were slightly more stimulatory than OX62− cells. Thus, FL is a useful cytokine for obtaining large quantities of functional rat DC subsets in vitro.
Bone marrow CD34+ progenitor cells stimulated with stem cell factor and GM-CSF have the capacity to activate IgD− B cells through direct cellular interaction
Authors: Hirohata Shunsei , Yanagida Tamiko , Tomita Tetsuya , Yoshikawa Hideki , Ochi Takahiro
Published: September 2022

Recent studies have suggested the involvement of bone marrow in the pathogenesis of rheumatoid arthritis (RA), in which proliferation of monocyte-lineage cells (MLC) as well as local B cell activation in the synovium play an important role. Here, we show that bone marrow-derived MLC have the capacity to activate human peripheral blood IgD− B cells. Bone marrow CD34+ cells from RA patients that had been stimulated with stem cell factor and GM-CSF for 3–4 weeks (>90% CD14+ HLA-DR+ cells, <0.5% CD19+ B cells, and <0.5% CD3+ T cells; MLC) induced the production of IgG much more effectively than that of IgM by highly purified B cells from healthy donors in the presence of IL-2 and IL-10. CD34+ cells from cord blood or from bone marrow of osteoarthritis patients also displayed the capacity to induce IgG production. The induction of IgG production by the bone marrow-derived MLC was markedly decreased when they were separated from B cells by a membrane filter. The bone marrow-derived MLC interacted preferentially with IgD− B cells to induce IgG production. These results indicate that upon stimulation with stem cell factor and GM-CSF, CD34+ progenitor cells differentiate into MLC that activate preferentially IgD− B cells through direct cellular interactions to produce IgG. Therefore, the data suggest that the accelerated recruitment of MLC from the bone marrow to the synovium might play a role in the local B cell activation in RA.
Human neutrophil defensins induce lung epithelial cell proliferation in vitro
Authors: Aarbiou Jamil , Ertmann Marloes , van Wetering Sandra , van Noort Peter , Rook Denise , Rabe Klaus F , Litvinov Sergey V , van Krieken J Han J M , de Boer Willem I , Hiemstra Pieter S
Published: September 2022

Repair of injured airway epithelium is often accompanied by an influx of leukocytes, and these cells have been suggested to contribute to the repair process. The aim of the present study was to investigate the effect of neutrophil defensins—antimicrobial peptides present in large amounts in the neutrophil— on proliferation of cultured lung epithelial cells. Neutrophil defensins at 4–10 μg/ml enhanced proliferation of the A549 lung epithelial cell line as assessed using cell counting, BrdU incorporation, and the tetrazolium salt MTT assay. Higher, cytotoxic concentrations of defensins decreased cell proliferation. Whereas defensin-induced cell proliferation was not inhibited by the EGF receptor tyrosine kinase inhibitor AG1478, it was completely inhibited by the mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor U0126, suggesting that defensins mediate cell proliferation via an EGF receptor-independent, MAP kinase signaling pathway. Although the cytotoxic effect of defensins was inhibited by α1-proteinase inhibitor, the defensin-induced cell proliferation was not affected. These data suggest that neutrophil defensins may possibly be involved in epithelial repair in the airways by inducing lung epithelial cell proliferation.
Dipeptidyl peptidase IV (CD26) on T cells cleaves the CXC chemokine CXCL11 (I-TAC) and abolishes the stimulating but not the desensitizing potential of the chemokine
Authors: Ludwig Andreas , Schiemann Florian , Mentlein Rolf , Lindner Buko , Brandt Ernst
Published: September 2022

Dipeptidyl peptidase IV (DPP IV/CD26) is a costimulatory molecule as well as a protease highly expressed on T cells. Purified DPP IV has been recognized to inactivate peptide hormones, neuropeptides, and some chemokines by cleavage behind a proline residue at the penultimate N-terminal amino acid position. Here, we identified another substrate for DPP IV among the chemokine family: the interferon-inducible T cell α chemoattractant (I-TAC/CXCL11). Using a specific DPP IV inhibitor, we demonstrate that DPP IV is responsible for the cleavage of the chemokine by PHA/IL-2-treated T cells. As PHA/IL-2-treated T cells also express the CXCL11 receptor (CXCR3), we investigated whether truncation of CXCL11 would modulate its biological activity for these cells. Truncated CXCL11 [CXCL11(3–73)] had an eightfold reduced potential to bind and to regulate CXCR3, but was completely inactive in calcium flux and chemotaxis assays. However, consistent with its reduced but still considerable ability to down-regulate CXCR3, truncated CXCL11 desensitized T cell chemotaxis in response to the intact chemokine. Hence, CXCL11-induced T cell recruitment may be regulated by DPP IV-mediated proteolytic inactivation of CXCL11 and furthermore by desensitization of T cells via the degradation product CXCL11(3–73).
Expansion of dendritic cell precursors from human CD34+ progenitor cells isolated from healthy donor blood; growth factor combination determines proliferation rate and functional outcome
Authors: Bontkes Hetty J , de Gruijl Tanja D , Schuurhuis Gert Jan , Scheper Rik J , Meijer Chris J L M , Hooijberg Erik
Published: September 2022

CD34+ haematopoietic progenitor cells, which circulate at extremely low frequencies in peripheral blood, are used to generate dendritic cells (DC) in vitro. Here, we describe a method to grow large numbers of DC precursors from these low frequent cells. Different combinations of early acting haematopoietic growth factors supported expansion of CD34+ cells. CD1a+ DC derived from precursors, expanded in fms-like tyrosine kinase-3 ligand (Flt3-L), stem-cell factor (SCF), interleukin (IL)-3, and IL-6, were less potent antigen-presenting cells (APC) compared to CD1a+ DC derived from precursors expanded in Flt3-L, trombopoietine (TPO), and SCF. Furthermore, the latter produced high levels of IL-12 and low levels of IL-10, a cytokine profile favorable for the priming cytotoxic T cells. In contrast, a mean increase of total cell number of 453-fold was obtained with Flt3-L, SCF, IL-3, and IL-6, and this increase was only 38-fold with Flt3-L, TPO, and SCF. Sequential cultures of both cocktails resulted in high numbers of potent APC, which can be useful DC-based cancer vaccines.
Identification of downstream genes up-regulated by the tumor necrosis factor family member TALL-1
Authors: Xu Liang-Guo , Wu Min , Hu Jiancheng , Zhai Zhonghe , Shu Hong-Bing
Published: September 2022

TALL-1 is a member of the tumor necrosis factor family that binds to BCMA, TACI, and BAFF-R, three receptors mostly expressed by mature B lymphocytes. Previous studies have shown that the TALL-1 signaling is critically involved in B cell proliferation, maturation, and progression of lupus-like, autoimmune diseases. In this report, we performed cDNA subtractive hybridization experiments to identify downstream genes up-regulated by TALL-1. These experiments indicated that 10 genes, including interleukin (IL)-10, lymphocyte activation gene-1 (LAG-1), GCP-2, PBEF, ferritin, PIM-2, TFG, CD27 ligand, DUSP5, and archain, were up-regulated at the mRNA level by TALL-1 stimulation in B lymphoma RPMI-8226 cells and/or primary B lymphocytes. We also demonstrated that TALL-1 activated transcription of IL-10 and LAG-1 in a nuclear factor-κB-dependent manner in reporter gene assays. Moreover, our findings indicated BAFF-R, but not TACI, could dramatically up-regulate IL-10 secretion by RPMI-8226 cells. The identification of TALL-1-up-regulated genes will help explain the mechanisms of TALL-1-triggered biological and pathological effects and to identify molecular targets for intervention of lupus-like autoimmune diseases.
Macrophage accumulation at a site of renal inflammation is dependent on the M-CSF/c-fms pathway
Authors: Le Meur Yannick , Tesch Gregory H , Hill Prudence A , Mu Wei , Foti Rita , Nikolic-Paterson David J , Atkins Robert C
Published: September 2022

Production of macrophage-colony stimulating factor (M-CSF), the major macrophage growth factor, is increased in tissues during inflammation. Therefore, w determined whether M-CSF, acting through its receptor c-fms, contributes to macrophage accumulation at a site of tissue injury. Daily treatment with anti-c-fms or control antibody was given to mice with renal inflammation resulting from unilateral ureteric obstruction (UUO). Following UUO, kidney M-CSF mRNA increased in association with macrophage accumulation (days 1, 5, and 10) and local macrophage proliferation (days 5 and 10). Anti-c-fms treatment caused a minor inhibition of monocyte recruitment at day 1, reduced macrophage accumulation by 75% at day 10, but did not affect blood monocyte counts or the CD4 and CD8 lymphocytic infiltrate. Prevention of macrophage accumulation by anti-c-fms treatment was associated with a 90% reduction in local macrophage proliferation at days 5 and 10 without evidence of increased macrophage apoptosis. Therefore, M-CSF/c-fms signaling plays a key role in macrophage accumulation during tissue injury.
The IL-12 response to herpes simplex virus is mainly a paracrine response of reactive inflammatory cells
Authors: Kumaraguru Udayasankar , Rouse B T
Published: September 2022

Herpes simplex virus (HSV) infection results in rapid and sustained up-regulation of interleukin (IL)-12, but the primary cellular source of IL-12 after HSV infection is unknown. We demonstrate that this cytokine largely derives from inflammatory cells rather than from productively infected epithelial cells. For optimal IL-12 induction, epithelial cells needed to be infected with replication-competent virus, and cells needed to be able to synthesize proteins. Our results also indicate that HSV-infected cells generate intermediary products that signal recruited inflammatory cells, which themselves were not HSV-infected, to generate IL-12. Possible mechanisms by which infected cells communicate with inflammatory cells to cause IL-12 production are discussed.
IL-13 signal transduction in human monocytes: phosphorylation of receptor components, association with Jaks, and phosphorylation/activation of Stats
Authors: Roy Biswajit , Bhattacharjee Ashish , Xu Bo , Ford Dwayne , Maizel Abby L , Cathcart Martha K
Published: September 2022

Interleukin (IL)-13 regulates monocyte function and is a potent stimulator of 15-lipoxygenase expression. In different cell types, the functional IL-13 receptor complex can be comprised of variable protein components and has not been thoroughly examined in human monocytes. Here, we identify the receptor components and upstream signaling events initiated by IL-13 in primary human blood monocytes. Th expression, phosphorylation and associated Jak kinases of the known, variable receptor components, IL-4Rα, IL-2Rγc, IL-13Rα1 and IL-13Rα2, were examined. We determined that IL-4Rα and IL13Rα1 are phosphorylated upon exposure to IL-13. Although IL-2Rγc is also expressed, it is not phosphorylated upon exposure to IL-13. Evaluation of the presence of IL-13Rα2 failed to reveal significant mRNA or protein expression. Earlier, our laboratory showed that IL-13 induced the phosphorylation of Jak2 and Tyk2 in monocytes and that expression of both Jaks was essential for downstream signaling by IL-13. Here, we report that Jak2 is associated with IL-4Rα, and Tyk2 is associated with the IL-13Rα1 component of the IL-13 receptor complex. Additionally, Stat proteins 1α, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. Further, the nuclear translocation and DNA binding of each of these Stats were induced by IL-13. These data represent the first complete report of the functional IL-13 receptor complex and early signaling events in human monocytes. This information is critical for understanding the IL-13 response of monocytes in inflammation.
Role of the autocrine chemokines MIP-1α and MIP-1β in the metastatic behavior of murine T cell lymphoma
Authors: Menten Patricia , Saccani Alessandra , Dillen Chris , Wuyts Anja , Struyf Sofie , Proost Paul , Mantovani Alberto , Wang Ji Ming , Van Damme Jo
Published: September 2022

The ESb-MP T-cell line is a highly malignant murine lymphoma, which preferentially metastasizes toward the kidney. This could be a result of the local production of monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T expressed and secreted (RANTES), which are chemotactic for ESb-MP cells. Here, we demonstrate that ESb-MP cells are already responsive to the chemotactic activity of macrophage inflammatory protein-1α (MIP-1α) and MIP-1β from 1 ng/ml onward. Moreover, upon stimulation with lipopolysaccharide (LPS) or virus, ESb-MP cells themselves produce significant amounts of MIP-1 (∼200 ng/ml). Indeed, the major autocrine chemoattractants, isolated from ESb-MP cells, were intact MIP-1α and MIP-1β. Pretreatment with LPS or addition of MIP-1 inhibited the in vitro migration of ESb-MP cells toward various chemokines. Moreover, compared with untreated lymphoma cells, LPS-treated cells produced significantly less metastasis in mice. The results represented here suggest that the role of chemokines in attracting tumor cells at secondary sites depends on a balance between autocrine-produced and tissue-derived chemokines. This delicate balance should be considered in the design of antichemokine strategies in different tumor types.
Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses
Authors: Parrish-Novak Julia , Foster Donald C , Holly Richard D , Clegg Christopher H
Published: September 2022

Interleukin (IL)-21 was recently discovered using a functional cloning approach based on expression of its receptor. It is similar in domain organization and primary sequence to IL-2 and IL-15. Like these cytokines, IL-21 uses the common γ chain of the IL-2/15 receptor, which forms a heterodimeric receptor complex with IL-21R. IL-21 is produced by activated T cells, and it influences proliferation of T and B cells and cytolytic activity of natural killer cells. The elucidation of the unique biological effects of IL-21 represents an intense area of interest in current cytokine biology.
Disruption of the Nramp1 (also known as Slc11a1) gene in Kupffer cells attenuates early-phase, warm ischemia-reperfusion injury in the mouse liver
Authors: Wyllie Samuel , Seu Philip , Gao Feng Qin , Gros Phillippe , Goss John A
Published: September 2022

As the natural resistance-associated macrophage protein 1 Nramp1 (also known as Slc11a1) modulates Kupffer cell (KC) activation, and KC are responsible for the early phase of warm ischemia/reperfusion (I/R) to the liver, we hypothesized that livers of Nramp1−/− mice will be protected from early-phase I/R injury compared with livers of Nramp1+/+ mice. To test our hypothesis, we induced partial warm ischemia to the livers of Nramp1+/+ and Nramp1−/− mice for 45 min of by clamping the hilum of the median and left lateral lobes, followed by 30 or 60 min of reperfusion. Plasma glutamate oxaloacetate transaminase (pGOT) activity and tumor necrosis factor α (TNF-α) levels were measured, and liver sections were stained for polymorphonuclear leukocyte (PMN) accumulation. After 45 min of ischemia and 30/60 min of reperfusion of Nramp1+/+ and Nramp1−/− mice livers, we found significant increases in plasma pGOT activity and TNF-α levels in Nramp1+/+ mice at 30 and 60 min of reperfusion, respectively, compared with sham controls and all Nramp1−/− mice. A significant accumulation of PMNs was also found in livers of Nramp1+/+ mice at 60 min of reperfusion compared with all other groups. We have shown that disruption of the Nramp1 gene attenuates I/R injury to the mouse liver during the early phase of warm I/R injury. An increased understanding of the role played by Nramp1 is particularly important in the liver, as this organ is subjected to a wide variety of injuries during hemorrhagic shock, partial resections, and transplantation.
Role of CD80, CD86, and CTLA4 on mouse CD4+ T lymphocytes in enhancing cell-cycle progression and survival after activation with PMA and ionomycin
Authors: Mukherjee Sambuddho , Maiti Prasanta K , Nandi Dipankar
Published: September 2022

Cell surface interactions between the T cell costimulatory receptors, CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA4), with their cognate ligands, CD80 and CD86, on antigen-presenting cells play an important role in T cell activation. Although CD80 and CD86 are induced on T cells after activation, not much is known about their role in modulating T cell function. We show that CD80, CD86, and CTLA4 are induced on purified CD4+ T cells after in vitro activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and they play an essential role for proliferation and survival. Blockade of CTLA4-CD80/CD86 interactions greatly reduces PMA and ionomycin-mediated mouse CD4+ T cell activation. The three key features of this inhibition of activation are: First, late events in T cell activation (after 18 h) are affected; second, these cells do not undergo anergy; and third, CD4+CD25+ regulatory T cells are not responsible. Activation of T cells with PMA and ionomycin together with CTLA4-CD80/CD86 blockade results in decreased induction of CD25 and Bcl-XL, reduced interleukin (IL)-2, and enhanced transforming growth factor-β (TGF-β) production. Furthermore, extended CTLA4-CD80/CD86 blockade results in decreased cell-cycle progression and enhanced apoptosis in a large proportion of cells. This inhibition of T cell proliferation can be rescued completely with anti-CD28 or IL-2 and partially with TGF-β antagonists. This study reveals a functional role for CD80, CD86, and CTLA4 on CD4+ T lymphocytes and sheds light on the mechanisms by which these molecules enhance activation and survival with PMA and ionomycin.
Cyclosporin A inhibits dendritic cell maturation promoted by TNF-α or LPS but not by double-stranded RNA or CD40L
Authors: Duperrier K , Farre A , Bienvenu J , Bleyzac N , Bernaud J , Gebuhrer L , Rigal D , Eljaafari A
Published: September 2022

Here, we investigated the influence of cyclosporin A (CsA) on dendritic cell (DC) generation. With this aim, human DC were propagated from monocytes in serum-free medium with granulocyte macrophage-colony stimulating factor and interleukin-4. DC were then exposed to tumor necrosis factor α (TNF-α) for maturation. Our results show that CsA does not impair commitment of monocytes into DC, as assessed by loss of CD14 and increase of CD40 and CD1a. However, TNF-α-induced DC maturation was affected, as CsA-treated DC expressed lower levels of human leukocyte antigen and costimulatory molecules but sustained levels of CD1a, and less DC expressed DC-lysosomal-associated-membrane-protein (LAMP) and CD83. Accordingly, CsA inhibited the allostimulatory and accessory cell functions of DC. Surprisingly, when other maturation stimuli were used, we observed that CsA significantly inhibited maturation induced by lipopolysaccharides but not by polyribocytidylic acid or CD40 ligand, as assessed by DC phenotype and functions. Therefore, our results indicate that CsA may differentially affect DC maturation.
Chronic ethanol consumption by mice results in activated splenic T cells
Authors: Song Kejing , Coleman Ruth A , Zhu Xiaoyan , Alber Carol , Ballas Zuhair K , Waldschmidt Thomas J , Cook Robert T
Published: September 2022

Previous studies have shown that T cells from human alcoholics overexpress activation or memory markers such as human leukocyte antigen-DR, CD45RO, CD57, and CD11b and may have reduced levels of CD62L. In those studies, we demonstrated that the increased CD57+ T cell population rapidly produces interferon-γ (IFN-γ) and tumor necrosis factor α, independent of a second signal requirement, consistent with an increased effector T cell population. In contrast to the length of alcohol abuse by human alcoholics, most work with mice has involved 2-week ethanol exposures or less, which result in decreased IFN-γ responses. In the present work, we have evaluated C57Bl/6 or BALB/c mice, which were administered 20% w/v ethanol in water for 3–13 weeks. In these mice, rapid cytoplasmic IFN-γ expression by T cells after stimulation through the T cell receptor was significantly increased versus normals. Studies of surface-activation markers showed that T cells from chronically ethanol-fed mice had reduced CD62L expression and an increased percentage of CD44hi T cells. The CD44hi subset was largely second signal-independent for secreted IFN-γ and interleukin (IL)-4 production at early times after stimulation. The enriched T cells of chronic ethanol mice secreted more IFN-γ and IL-4 than controls and equivalent IL-2 at early times after stimulation (6–24 h). The overall results support the concept that in humans and mice, chronic alcohol exposure of sufficient duration results in T cell activation or sensitization in vivo and an increased percentage of the effector/memory subset.
Diminution of experimental autoimmune uveoretinitis (EAU) in mice depleted of NK cells
Authors: Kitaichi Nobuyoshi , Kotake Satoshi , Morohashi Taiki , Onoé Kazunori , Ohno Shigeaki , Taylor Andrew W
Published: September 2022

To evaluate the potential role of NK1.1 (CD161c) cells in autoimmune uveoretinitis, we treated experimental autoimmune uveoretinitis (EAU)-susceptible mice with anti-CD161c antibodies (PK136) to deplete natural killer (NK) cells. Injection of anti-CD161c antibodies deleted NK cells from the peripheral blood of EAU-susceptible mice. The T cell proliferative response against the ocular autoantigen K2 was not suppressed in mice treated with anti-CD161c antibody when compared with T cells from control mice. Although mice treated with anti-CD161c developed EAU, the clinical severity on days 17 and 19 after induction of EAU was significantly mild in anti-CD161c-treated mice compared with control mice. In addition, the histopathological severity of EAU was significantly milder in mice treated with anti-CD161c antibodies than controls 21 days after induction of EAU. Our results indicate that the severity of EAU is augmented by NK1.1+ NK cells.
The Double Agent: NOB / RD
Authors: Davidson Michael
Published: September 2022

This essay explores the close relationship between the poet Robert Duncan and Norman O. Brown. Their long friendship and shared intellectual interests were generative for both, allowing Brown at one point to remark that the “poetry of Robert Duncan had made the writing of Love's Body possible.” Duncan responded in kind by featuring Brown in “Santa Cruz Propositions,” written while the poet was in residence at the University of California, Santa Cruz. That poem draws on Brown's theories of Eros as a daemonic power to criticize his (Duncan's) old friend, Denise Levertov, whose anti-war poetry he felt had grown shrill and hectoring. At the same time, the poem attempts to draw out Brown's Dionysian, poetic potential. Duncan made Norman O. Brown an unwitting co-conspirator in this effort by attempting to reveal the naked poet beneath the academic robes. Much of the essay is based on correspondence between the two figures.
Management of Chronic Subdural Hematoma: A Systematic Review and Component Network Meta-analysis of 455 Studies With 103 645 Cases
Authors: Henry Jack , Amoo Michael , Kissner Malia , Deane Thomas , Zilani Gulam , Crockett Matthew T. , Javadpour Mohsen
Published: September 2022

BACKGROUND:

Chronic subdural hematoma (CSDH) is a common neurosurgical condition with a high risk of recurrence after treatment.

OBJECTIVE:

To assess and compare the risk of recurrence, morbidity, and mortality across various treatments for CSDH.

METHODS:

A systematic review and meta-analysis was performed. PubMed/MEDLINE, EMBASE, SCOPUS, and Web of Science were searched from January 01, 2000, to July 07, 2021. The primary outcome was recurrence, and secondary outcomes were morbidity and mortality. Component network meta-analyses (CNMAs) were performed for surgical and medical treatments, assessing recurrence and morbidity. Incremental risk ratios (iRRs) with 95% CIs were estimated for each component.

RESULTS:

In total, 12 526 citations were identified, and 455 studies with 103 645 cases were included. Recurrence occurred in 11 491/93 525 (10.8%, 95% CI 10.2-11.5, 418 studies) cases after surgery. The use of a postoperative drain (iRR 0.53, 95% CI 0.44-0.63) and middle meningeal artery embolization (iRR 0.19, 95% CI 0.05-0.83) reduced recurrence in the surgical CNMA. In the pharmacological CNMA, corticosteroids (iRR 0.47, 95% CI 0.36-0.61) and surgical intervention (iRR 0.11, 95% CI 0.07-0.15) were associated with lower risk. Corticosteroids were associated with increased morbidity (iRR 1.34, 95% CI 1.05-1.70). The risk of morbidity was equivalent across surgical treatments.

CONCLUSION:

Recurrence after evacuation occurs in approximately 10% of cSDHs, and the various surgical interventions are approximately equivalent. Corticosteroids are associated with reduced recurrence but also increased morbidity. Drains reduce the risk of recurrence, but the position of drain (subdural vs subgaleal) did not influence recurrence. Middle meningeal artery embolization is a promising treatment warranting further evaluation in randomized trials.
Comparison of Flow-Redirection Endoluminal Device and Pipeline Embolization Device in the Treatment of Intracerebral Aneurysms
Authors: El Naamani Kareem , Saad Hassan , Chen Ching-Jen , Abbas Rawad , Sioutas Georgios S. , Amllay Abdelaziz , Yudkoff Clifford J. , Carreras Angeleah , Sambangi Abhijeet , Hunt Adam , Jain Paarth , Dougherty Jaime , Tjoumakaris Stavropoula I. , Gooch Michael R. , Herial Nabeel A. , Rosenwasser Robert H. , Zarzour Hekmat , Schmidt Richard F. , Jabbour Pascal M.
Published: September 2022

BACKGROUND:

The use of flow diverters for treating intracranial aneurysms has been widely used in the past decade; however, data comparing pipeline embolization device (PED; Medtronic Inc) and flow-redirection endoluminal device (FRED; MicroVention) in the treatment of intracranial aneurysms remain scarce.

OBJECTIVE:

To compare the outcomes of PED and FRED in the treatment of intracranial aneurysms.

METHODS:

This is a single-center retrospective review of aneurysms treated with PED and FRED devices. Patients treated with PED or FRED were included. Cases requiring multiple or adjunctive devices were excluded. Primary outcome was complete aneurysm occlusion at 6 months. Secondary outcomes included good functional outcome, need for retreatment, and any complication.

RESULTS:

The study cohort comprised 150 patients, including 35 aneurysms treated with FRED and 115 treated with PED. Aneurysm characteristics including location and size were comparable between the 2 cohorts. 6-month complete occlusion rate was significantly higher in the PED cohort (74.7% vs 51.5%;P= .017) but lost significance after inverse probability weights. Patients in the PED cohort were associated with higher rates of periprocedural complications (3.5% vs 0%;P= .573), and the rate of in-stent stenosis was approximately double in the FRED cohort (15.2% vs 6.9%;P= .172).

CONCLUSION:

Compared with PED, FRED offers modest 6-month occlusion rates, which may be due to aneurysmal and baseline patient characteristics differences between both cohorts. Although not significant, FRED was associated with a higher complication rate mostly because of in-stent stenosis. Additional studies with longer follow-up durations should be conducted to further evaluate FRED thrombogenicity.
The Round Trip Effect: Endogenous Transport Costs and International Trade
Authors: Wong Woan Foong
Published: September 2022

Container ships travel between a fixed set of origins and destinations in round trips, inducing a negative correlation in their freight rates. I study the implications of this round trip effect on international trade and trade policy. I identify this effect and develop an instrument using it to estimate the impact of transport costs on trade. I simulate counterfactual import tariff increases in a quantitative model and quantify the importance of endogenizing transport costs with respect to this effect: an exogenous transport costs model predicts a trade balance improvement from protectionist policies, while the round trip model finds the opposite. (JEL D22, F13, F14, L92, R41)
Correction to “Temperature and Decisions: Evidence from 207,000 Court Cases” and Reply to Spamann
Authors: Heyes Anthony , Saberian Soodeh
Published: September 2022

This paper evidenced the sensitivity of US immigration judge decisions to temperature in the city of arbitration on the date of a case's completion. This note serves to correct errors noted since publication. The results from both the main linear specifications are qualitatively unchanged, with estimated treatment effects similar in size to the original and retaining statistical significance at conventional levels. Some secondary results lose significance with the erosion of sample size. We also acknowledge the additional finding by Spamann (2022) with respect to external validity. (JEL K37, K41, Q54)
Why Is Europe More Equal than the United States?
Authors: Blanchet Thomas , Chancel Lucas , Gethin Amory
Published: September 2022

This article combines all available data to produce pretax and post-tax income inequality series in 26 European countries from 1980 to 2017. Our estimates are consistent with macroeconomic growth and comparable with US distributional national accounts. Inequality grew in nearly all European countries, but much less than in the US. Contrary to a widespread view, we demonstrate that Europe’s lower inequality levels cannot be explained by more equalizing tax and transfer systems. After accounting for indirect taxes and in-kind transfers, the US redistributes a greater share of national income to low-income groups than any European country. “Predistribution,” not “redistribution,” explains why Europe is less unequal than the United States. (JEL D31, E01, H23, H24, H50, I38)
Using 3D polylines to improve cone-beam CT-guided percutaneous transthoracic needle biopsy
Authors: Han Young-Min , Kim Kun Yung
Published: September 2022

Objectives:

To investigate the diagnostic accuracy of using 3D polylines (3DPs) to improve cone-beam CT (CBCT) virtual navigation (VN)-guided percutaneous transthoracic needle biopsies (PTNB) of pulmonary lesions.

Methods:

From May 2021 to November 2021, patients (81 males and 41 females; age, 65 ± 12 years) who underwent CBCT VN with 3DPs for PTNB of pulmonary lesions were retrospectively reviewed. Fluoroscopic visibility of target lesions was evaluated using captured images from a Bull’s eye view. Diagnostic accuracy was calculated, and complications were assessed.

Results:

The mean size of biopsied lesions was 23 ± 13 mm (range: 6–75 mm). Overall, 13.9% (17/122) were small pulmonary nodules (diameter ≤1 cm), and 68.0% (83/122) of biopsied lesions were fluoroscopic visible. The overall diagnostic accuracy was 94.3%. The diagnostic accuracy for visible and invisible lesions was 94.0 and 94.9%, respectively (p = 0.843), and 100% for small pulmonary nodules. Major complications occurred in 8.2% (10/122; eight pneumothorax with chest tube insertion, one hemoptysis with transfusion, and one air embolism) of patients.

Conclusion:

CBCT VN with 3DP guidance provide a real-time outline of pulmonary lesions, thus enabling a reliable and accurate PTNB.

Advances in knowledge:

3DP guidance could be useful technique for CBCT-guided PTNB, especially in small pulmonary nodules.