bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD40-mediated up-regulation of Toll-like receptor 4-MD2 complex on the surface of murine dendritic cells
Authors: Frleta Davor , Noelle Randolph J , Wade William F 
Published: September 2003

AbstractToll-like receptors (TLRs) recognize pathogen-associated molecular patterns, which are non-self macromolecular components of pathogens that allow the innate-immune system to recognize infection. TLRs are expressed on macrophages and dendritic cells (DC). TLR stimulation or CD40 agonists can induce inflammatory cytokine secretion from macrophages and DC, and promote DC maturation. The regulation of TLR expression by inflammation has begun to be explored. Our studies have focused on the regulation of TLR4 surface expression on DC. TLR4, along with the adaptor molecule MD2, is involved in the recognition of lipopolysaccharide (LPS). CD40 stimulation via cross-linked anti-CD40 monoclonal antibody (mAb) up-regulates TLR4-MD2 surface expression on a DC cell line (DC2.4) and on ex vivo-cultured splenic DC. LPS treatment down-regulated surface TLR4-MD2 on DC2.4 cells, but if combined with anti-CD40 mAb, increased TLR4-MD2 expression was observed. The increased TLR4-MD2 surface expression by any treatment did not correlate with TLR4 mRNA levels. The functional consequence of increased TLR4-MD2 expression following LPS and anti-CD40 treatment was examined. Although CD40 prestimulation did slightly enhance interleukin-12p70 secretion after LPS restimulation, simultaneous anti-CD40 mAb and LPS treatment, which up-regulates TLR4-MD2 complex, does not restore DC responsiveness to subsequent LPS.
Multinutrient undernutrition dysregulates the resident macrophage proinflammatory cytokine network, nuclear factor-κB activation, and nitric oxide production
Authors: Anstead Gregory M , Chandrasekar Bysani , Zhang Qiong , Melby Peter C 
Published: September 2003

AbstractWe have described previously a murine model of multinutrient undernutrition that reproduced the features of moderate human malnutrition and led to increased early dissemination of Leishmania donovani. Peritoneal cells from these malnourished mice produced decreased NO after stimulation with IFN-γ/LPS. We hypothesized that malnutrition may cause a deficit in NF-κB activation, a principal transcription pathway for inducible NO synthase and proinflammatory cytokines. Macrophages from malnourished mice, stimulated with IFN-γ/LPS, showed increased IL-6 production and decreased IL-10 and TNF-α production. Neutralization of TNF-α in macrophage cultures from the control mice mimicked the effect of malnutrition on NO and IL-10 production, whereas supplemental TNF-α added to cultures of macrophages from malnourished mice increased NO secretion. NF-κB nuclear binding activity in macrophages from the malnourished mice was reduced early after stimulation, but increased to supranormal values by 16- or 24-h poststimulation. Blocking NO production in the macrophages from the control mice reproduced the effect of malnutrition on the late activation of NF-κB, whereas supplemental NO decreased the late NF-κB activation in the malnourished mice. Thus, in macrophages from the malnourished mice, initial deficits in NF-κB activity probably lead to decreased TNF-α, which results in decreased NO; however, IL-6 is regulated independently from NF-κB and TNF-α. The late activation of NF-κB in the macrophages from malnourished mice is due to absence of negative feedback from NO.
Artificially controlled aggregation of proteins and targeting in hematopoietic cells
Authors: Rosén Hanna , Gao Ying , Johnsson Ellinor , Olsson Inge 
Published: September 2003

AbstractThe targeting mechanisms for granule proteins in hematopoietic cells are largely unknown. Aggregation is believed to be important for protein sorting-for-entry and sorting-by-retention in endocrine and neuroendocrine cells. We asked whether artificially induced multimerization/aggregation of chimeric proteins could affect their sorting in hematopoietic cells. A system was used that permits ligand-controlled intracellular oligomerization of hybrid proteins containing the FK506-binding protein (FKBP). The hybrid proteins ELA-(FKBP)3 with neutrophil elastase (ELA) and (FKBP∗)4-FCS-hGH with a furin cleavage site (FCS) and human growth hormone (hGH) were expressed in the myeloblastic 32D and the rat basophilic leukemia (RBL-1) hematopoietic cell lines. ELA alone is normally targeted to secretory lysosomes. However, the hybrid proteins and ligand-induced aggregates of them were constitutively secreted and not targeted. The hGH that was released at the FCS in (FKBP∗)4-FCS-hGH was also constitutively secreted. We conclude that protein multimerization/aggregation per se is not enough to facilitate sorting-for-entry to secretory lysosomes in hematopoietic cells and that improperly folded proteins may be eliminated from sorting by constitutive secretion.
Expression of the c-ErbB-2/HER2 proto-oncogene in normal hematopoietic cells
Authors: Leone Francesco , Perissinotto Eliana , Cavalloni Giuliana , Fonsato Valentina , Bruno Stefania , Surrenti Nadia , Hong Dengli , Capaldi Antonio , Geuna Massimo , Piacibello Wanda , Aglietta Massimo 
Published: September 2003

Abstract
The HER2/c-ErbB-2 proto-oncogene is overexpressed in 25–30% of human breast cancers. We previously reported the c-ErbB-2 transcript in mononuclear cells (MNC) from bone marrow (BM), peripheral blood (PB), and mobilized PB (MPB). Here, we describe extensively the expression pattern of c-ErbB-2 mRNA and protein in normal adult hematopoietic tissue and cord blood (CB)-derived cells. Quantitative reverse transcriptase-polymerase chain reaction shows that the c-ErbB-2 transcript is expressed in hematopoietic cells at low levels if compared with normal epithelial and breast cancer cells. The c-ErbB-2 protein was detected predominantly in MNC from PB and CB by Western blot analysis. Flow cytometry revealed that CD15+, CD14+, and glycophorin A+ subpopulations express c-ErbB-2 protein, whereas lymphocytes are c-ErbB-2-negative. The c-ErbB-2 expression is higher in CB MNC. More than 90% of BM- and MPB-derived CD34+ progenitors are c-ErbB-2-negative; by contrast, 5–40% of CB-derived CD34+ progenitors express c-ErbB-2. We found that c-ErbB-2 protein is up-regulated during cell-cycle recruitment of progenitor cells. Similarly, it increases in mature, hematopoietic proliferating cells. This study reports the first evidence that the c-ErbB-2 receptor is correlated to the proliferating state of hematopoietic cells. Studies in progress aim to clarify the role of c-ErbB-2 in regulation of this process in hematopoietic tissues.
How we detect microbes and respond to them: the Toll-like receptors and their transducers
Authors: Beutler B , Hoebe K , Du X , Ulevitch R J 
Published: September 2003

Abstract
Macrophages and dendritic cells are in the front line of host defense. When they sense host invasion, they produce cytokines that alert other innate immune cells and also abet the development of an adaptive immune response. Although lipolysaccharide (LPS), peptidoglycan, unmethylated DNA, and other microbial products were long known to be the primary targets of innate immune recognition, there was puzzlement as to how each molecule triggered a response. It is now known that the Toll-like receptors (TLRs) are the principal signaling molecules through which mammals sense infection. Each TLR recognizes a restricted subset of molecules produced by microbes, and in some circumstances, only a single type of molecule is sensed (e.g., only LPS is sensed by TLR4). TLRs direct the activation of immune cells near to and far from the site of infection, mobilizing the comparatively vast immune resources of the host to confine and defeat an invasive organism before it has become widespread. The biochemical details of TLR signaling have been analyzed through forward and reverse genetic methods, and full elucidation of the molecular interactions that transpire within the first minutes following contact between host and pathogen will soon be at hand.
Developmental markers of B cells are superior to those of T cells for identification of stages with distinct gene expression profiles
Authors: Hoffmann Reinhard , Seidl Thomas , Bruno Ludovica , Dugas Martin 
Published: September 2003

Abstract
B and T lymphocytes develop through a series of cellular stages, which are defined by recombination status of the immunoglobulin and T cell receptor loci and can be separated by analysis of cell-surface markers. We evaluated how well 26 and 41 samples from five and eight developmental stages of B and T cell development, respectively, could be correctly assigned to their lineage of origin and developmental stage by analysis of the expression of 13,026 genes and expressed sequence tags (ESTs). The RNA expression patterns of eight genes correctly classified all 67 samples as belonging to the B cell or to the T cell lineage. Ninety-two to 100% of B-lineage samples could be correctly assigned to the protein-defined developmental stage by the RNA expression pattern of 29 genes. By contrast, RNA expression patterns of 39 genes were necessary to correctly assign 85–100% of T-lineage samples to the correct developmental stage. The sets of genes used for these classifications contain ESTs as well as known genes that have not previously been associated with lymphocyte development. Graphical display of the classifications shows that B-lineage samples are well separated from T-lineage samples, and samples from the five stages of B cell development are well separated from each other. By contrast, samples from the eight stages of T cell development cannot be separated precisely. We conclude that the protein markers currently widely used for separating stages of B cell development better identify molecularly distinct stages than those used for separating stages of T cell development.
Expression of glucocorticoid resistance following social stress requires a second signal
Authors: Avitsur Ronit , Padgett David A , Dhabhar Firdaus S , Stark Jennifer L , Kramer Kari A , Engler Harald , Sheridan John F 
Published: September 2003

Abstract
Stimulation of splenocytes from socially stressed mice [social disruption (SDR)] with Gram-negative bacterial lipopolysaccharide (LPS) revealed a state of functional glucocorticoid (GC) resistance. LPS-stimulated splenocytes were less sensitive to the inhibitory effects of corticosterone. This study demonstrated that activation signals were required for the expression of splenic GC resistance. The results demonstrated that six cycles of SDR induced splenomegaly and increased the number of CD11b-positive monocytes. SDR also increased the viability of cultured, nonstimulated splenocytes, and addition of corticosterone reduced the viability of these cells in a dose-dependent manner. However, following stimulation with LPS, the sensitivity of SDR splenocytes to GC was reduced. Similar results were obtained using lipid A, a fraction of the LPS molecule that binds to Toll-like receptor (TLR)4. Furthermore, C3H/HeJ mice that do not possess a functional TLR4 molecule responded to SDR with an increased number of CD11b-positive monocytes in the spleen and increased viability of nonstimulated splenocytes. However, neither LPS nor lipid A stimulation resulted in the expression of GC resistance. Together, these findings suggest that the expression of GC resistance in response to SDR requires a second signal that can be provided by ligation of TLR4.
CD44, α4 integrin, and fucoidin receptor-mediated phagocytosis of apoptotic leukocytes
Authors: Johnson Jacob D , Hess Krista L , Cook-Mills Joan M 
Published: September 2003

AbstractVarious types of phagocytes mediate the clearance of apoptotic cells. We previously reported that human and murine high endothelial venule (HEV) cells ingest apoptotic cells. In this report, we examined endothelial cell fucoidin receptor-mediated phagocytosis using a murine endothelial cell model mHEV. mHEV cell recognition of apoptotic leukocytes was blocked by fucoidin but not by other phagocytic receptor inhibitors such as mannose, fucose, N-acetylglucosamine, phosphatidylserine (PS), or blocking anti-PS receptor antibodies. Thus, the mHEV cells used fucoidin receptors for recognition and phagocytosis of apoptotic leukocytes. The fucoidin receptor-mediated endothelial cell phagocytosis was specific for apoptotic leukocytes, as necrotic cells were not ingested. This is in contrast to macrophages, which ingest apoptotic and necrotic cells. Endothelial cell phagocytosis of apoptotic cells did not alter viable lymphocyte migration across these endothelial cells. Antibody blocking of CD44 and α4 integrin on the apoptotic leukocyte inhibited this endothelial cell phagocytosis, suggesting a novel function for these adhesion molecules in the removal of apoptotic targets. The removal of apoptotic leukocytes by endothelial cells may protect the microvasculature, thus ensuring that viable lymphocytes can successfully migrate into tissues.
The cannabinoid system and immune modulation
Authors: Klein Thomas W , Newton Cathy , Larsen Kellie , Lu Lily , Perkins Izabella , Nong Liang , Friedman Herman 
Published: September 2003

Abstract
Studies on the effects of marijuana smoking have evolved into the discovery and description of the endocannabinoid system. To date, this system is composed of two receptors, CB1 and CB2, and endogenous ligands including anandamide, 2-arachidonoyl glycerol, and others. CB1 receptors and ligands are found in the brain as well as immune and other peripheral tissues. Conversely, CB2 receptors and ligands are found primarily in the periphery, especially in immune cells. Cannabinoid receptors are G protein-coupled receptors, and they have been linked to signaling pathways and gene activities in common with this receptor family. In addition, cannabinoids have been shown to modulate a variety of immune cell functions in humans and animals and more recently, have been shown to modulate T helper cell development, chemotaxis, and tumor development. Many of these drug effects occur through cannabinoid receptor signaling mechanisms and the modulation of cytokines and other gene products. It appears the immunocannabinoid system is involved in regulating the brain-immune axis and might be exploited in future therapies for chronic diseases and immune deficiency.
Divergence in NK cell and cyclic AMP regulation of T cell CD40L expression in asthmatic subjects
Authors: Wingett Denise , Nielson Christopher P 
Published: September 2003

AbstractT cells are central in the pathogenesis of asthma, and the associated ligand, CD40L, plays an important role by increasing production of immunoglobulin E and inflammatory mediators. β-Adrenoceptor agonists are commonly used in asthma, although little is known regarding effects on CD40L expression and T cell activation. Here, we demonstrate that cyclic adenosine monophosphate (cAMP) and β-adrenoceptor agonists differentially regulate CD40L in asthma. cAMP increased naïve T cell CD40L expression in asthmatics (9.8±8.5 increase in percent CD40L-positive cells), and expression in control subjects was inhibited (7.1±6.0 decrease in percent CD40L-positive cells; P&lt; 0.05). Cell depletion and reconstitution experiments were used to determine that cAMP enhancement of CD40L required cell-to-cell contact with an asthma-associated natural killer (NK) cell subset. The NK cell subset expressed elevated levels of CD95, and in vitro-generated CD95+ NK2 cells also produced similar effects on CD40L expression. Our findings suggest that a subset of NK cells with elevated CD95 expression is associated with asthma and can reverse cAMP inhibitory effects on T cell CD40L with the potential to increase disease exacerbation.
Antibiotic cyclic AMP signaling by “primed” leukocytes confers anti-inflammatory cytoprotection
Authors: Abeyama Kazuhiro , Kawahara Ko-ichi , Iino Satoshi , Hamada Takashi , Arimura Shin-ichiro , Matsushita Kenji , Nakajima Toshihiro , Maruyama Ikuro 
Published: September 2003

AbstractThe mechanism underlying anti-inflammatory effects of macrolide antibiotics remains uncertain. In this study, we first show the evidences concerning the possible link between leukocytic cyclic adenosine monophosphate (cAMP) signaling and the mechanism of anti-inflammatory, cytoprotective actions of macrolides. The clinical range of macrolides (i.e., erythromycin, roxithromycin, and clarithromycin) preferentially inhibited nuclear factor-κB activation mediated by reactive oxygen intermediates, inducing cAMP-dependent signaling [i.e., cAMP and cAMP-responsive element-binding protein (CREB)] by “primed” but not “resting” leukocytes. In this context, cAMP/CREB inhibition with adenosine 3′:5′-cyclic monophosphothioate, rp-isomer (rp-cAMPs) and CREB decoy oligonucleotides reduced the anti-inflammatory actions of macrolides. These results thus indicate that macrolide-induced cAMP/CREB signaling, selectively by primed leukocytes, plays a major role in the mechanism of anti-inflammatory actions of macrolides.
Sepsis-induced SOCS-3 expression is immunologically restricted to phagocytes
Authors: Grutkoski P S , Chen Y , Chung C S , Ayala A 
Published: September 2003

AbstractWe have shown that immune cells from septic mice exhibit a suppressed response to exogenous stimuli in vitro. The suppressors of the cytokine signaling (SOCS) family are proteins that block intracellular signaling and can be induced by inflammatory mediators. Therefore, we hypothesized that SOCS-3 is up-regulated in immune cells in response to a septic challenge induced by cecal ligation and puncture (CLP). Mice were subjected to CLP or sham-CLP, and 2–48 h later, the blood, thymus, spleen, lung, and peritoneal leukocytes were harvested and examined. SOCS-3 was undetectable in thymocytes or blood leukocytes. In contrast, SOCS-3 was up-regulated in the spleen, lung, and peritoneal leukocytes in a time-dependent manner. Further examination revealed that only the macrophages and neutrophils expressed SOCS-3. These data suggest that cytokines and bacterial toxins present during sepsis have the ability to suppress the cytokine and/or lipopolysaccharide response and the function of immune cells by up-regulating SOCS-3.
Regulation of TCR-mediated T cell activation by TNF-RII
Authors: Aspalter Rosa Maria , Eibl Martha Marianne , Wolf Hermann Maximilian 
Published: September 2003

Abstract
In the present study, we investigated the role of tumor necrosis factor receptor II (TNF-RII) in human T cell activation induced via the T cell receptor (TCR) in an antigen-presenting cell-independent system. Our results confirm that interaction of TNF-α with TNF-RII but not TNF-RI is directly costimulatory to TCR-mediated T cell activation, thereby augmenting T cell proliferation, expression of T cell activation markers (CD25, human leukocyte antigen-DR, TNF-RII), and secretion of cytokines such as interferon-γ and TNF-α. In contrast to the well-defined costimulatory molecule CD28, costimulation via TNF-RII showed significant differences in kinetics, requirement for cross-linking, redundancy of intracellular signaling pathways involved, and the capacity to induce interleukin (IL)-2, IL-10, and IL-13 secretion. In addition, cross-linking TNF-RII had the capacity to down-regulate TCR/CD28-induced Ca++ mobilization, IL-2 mRNA expression, and IL-2 and IL-10 secretion. Taken together, our findings demonstrate that TNF-RII plays a unique role among the T cell costimulatory molecules, as TNF-RII ligation can have positive and negative effects on TCR-dependent signaling. TNF-RII cross-linking has an inhibitory effect on early TCR signaling events proximal to induction of Ca++ flux, which ultimately leads to modulation of the T cell cytokine pattern expressed.
Prostaglandin E2 inhibits production of the inflammatory chemokines CCL3 and CCL4 in dendritic cells
Authors: Jing Huie , Vassiliou Evros , Ganea Doina 
Published: September 2003

AbstractDendritic cells bridge innate and adaptive immunity and participate in both responses. Upon capture of pathogens, dendritic cells release inflammatory cytokines and chemokines, attracting other immune cells to the infection site. Anti-inflammatory cytokines, glucocorticoids, anti-inflammatory neuropeptides, and lipid mediators such as prostaglandin E2 (PGE2) limit and control the inflammatory response. In this study we report that exogenous PGE2 inhibits CCL3 (MIP-1α) and CCL4 (MIP-1β) expression and release from dendritic cells stimulated with either lipopolysaccharide (LPS), a TLR4 ligand, or peptidoglycan, a TLR2 ligand. The inhibition is dose-dependent and occurs at both the mRNA and protein levels. The inhibitory effect is mediated through EP2 and EP4 receptors and requires the presence of PGE2 at the time of LPS stimulation. Intraperitoneal administration of PGE2 together with LPS results in a reduction in the levels of CCL3 and CCL4 released in the peritoneal fluid, a reduction in the number of dendritic cells accumulating in the peritoneal cavity, and a reduction in CCL3 amount per cell in the peritoneal cell population. These results suggest that one of the mechanisms by which endogenous PGE2 acts as an anti-inflammatory agent, is the inhibition of inflammatory chemokine release from activated dendritic cells, preventing the excess accumulation of activated immune cells.
A key role of C5a/C5aR activation for the development of sepsis
Authors: Riedemann Niels C , Guo Ren-Feng , Ward Peter A 
Published: September 2003

AbstractIn recent studies, evidence has been provided for complement activation early during the onset of experimental sepsis. Excessive production of the anaphylatoxin C5a thereby appears to elicit various harmful effects. Blockade of C5a or C5a receptor (C5aR) at the start of experimental sepsis has been demonstrated to greatly improve survival in rodents. There is evidence that C5a, during the onset of sepsis, enhances the production of various proinflammatory mediators in different cell types. Besides its known, other proinflammatory effects, recent work suggested an inhibitory role of C5a for innate-immune functions of phagocytic cells (phagocytosis, reactive oxygen species production, chemotaxis) during experimental sepsis. This review article provides an overview of the important role of C5a/C5aR activation for the onset and development of sepsis.
Tumor cell-induced deactivation of human monocytes
Authors: Mytar Bożenna , Wołoszyn Maria , Szatanek Rafał , Baj-Krzyworzeka Monika , Siedlar Maciej , Ruggiero Irena , Więckiewicz Jerzy , Zembala Marek 
Published: September 2003

AbstractAlthough blood monocytes exhibit significant cytotoxic activity against tumor cells, the function of tumor infiltrating macrophages (TIM) is depressed in cancer patients. This study addresses the question of how the antitumor response of human monocytes, assessed by production of cytokines (tumor necrosis factor α, TNF; IL-10; IL-12p40) and cytotoxicity, is altered by exposure to cancer cells. Tumor cell−pre-exposed monocytes restimulated with tumor cells showed significantly decreased production of TNF, IL-12, increased IL-10 (mRNA and release) and inhibition of IL-1 receptor-associated kinase-1 (IRAK-1) expression. This down-regulation of cytokine production was selective, as the response of pre-exposed monocytes to lipopolysaccharide (LPS) was unaffected. Treatment of tumor cell−pre-exposed monocytes with hyaluronidase (HAase) improved their depressed production of TNF, while HAase-treated cancer cells did not cause monocyte dysfunction. The response of hyaluronan (HA)−pre-exposed monocytes to stimulation with tumor cells was also inhibited. Cytotoxic activity of monocytes pretreated with cancer cells was also decreased. This study shows that tumor cells selectively deactivate monocytes and suggests that tumor cell-derived HA by blocking CD44 on monocytes inhibits their antitumor response. These observations may provide some explanation for the depressed function of TIM in human malignancy.