bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet Endothelial Cell Adhesion Molecule Deficiency or Blockade Significantly Reduces Leukocyte Emigration in a Majority of Mouse Strains
Authors: Schenkel Alan R. , Chew Tina W. , Muller William A. 
Published: April 2014

Abstract
PECAM is a molecule used specifically during the diapedesis step when neutrophils and monocytes leave the blood compartment. Anti-PECAM reagents, such as Abs and soluble fusion proteins, block diapedesis both in vivo and in vitro. However, the PECAM knockout mouse in C57BL/6 strain has no serious defects in most models of inflammation. We show in this study that the same PECAM knockout backcrossed into the FVB/n strain clearly has reduced leukocyte emigration in two models of inflammation. Furthermore, we show that anti-PECAM reagents can block leukocyte emigration in several other wild-type strains of mice like FVB/n, SJL, and the outbred strain Swiss Webster. This clearly shows that the C57BL/6 strain is uniquely able to compensate for the loss of PECAM function. Murine models of inflammatory disease that have been studied using C57BL/6 mice should be re-evaluated using FVB/n or other mouse strains to determine whether PECAM plays a role in those models.
IL-5 and Granulocyte-Macrophage Colony-Stimulating Factor Activate STAT3 and STAT5 and Promote Pim-1 and Cyclin D3 Protein Expression in Human Eosinophils
Authors: Stout Barbara A. , Bates Mary Ellen , Liu Lin Ying , Farrington Natasha N. , Bertics Paul J. 
Published: April 2014

Abstract
Allergic inflammation is characterized by elevated eosinophil numbers and by the increased production of the cytokines IL-5 and GM-CSF, which control several eosinophil functions, including the suppression of apoptosis. The JAK/STAT pathway is important for several functions in hemopoietic cells, including the suppression of apoptosis. We report in this study that STAT3, STAT5a, and STAT5b are expressed in human eosinophils and that their signaling pathways are active following IL-5 or GM-CSF treatment. However, in airway eosinophils, the phosphorylation of STAT5 by IL-5 is reduced, an event that may be related to the reduced expression of the IL-5Rα on airway eosinophils. Furthermore, IL-5 and GM-CSF induced the protein expression of cyclin D3 and the kinase Pim-1, both of which are regulated by STAT-dependent processes in some cell systems. Pim-1 is more abundantly expressed in airway eosinophils than in blood eosinophils. Because Pim-1 reportedly has a role in the modulation of apoptosis, these results suggest that Pim-1 action is linked to the suppression of eosinophil apoptosis by these cytokines. Although cyclin D3 is known to be critical for cell cycle progression, eosinophils are terminally differentiated cells that do not proceed through the cell cycle. Thus, this apparent cytokine regulation of cyclin D3 suggests that there is an alternative role(s) for cyclin D3 in eosinophil biology.
CD56bright NK Cells Are Enriched at Inflammatory Sites and Can Engage with Monocytes in a Reciprocal Program of Activation
Authors: Dalbeth Nicola , Gundle Roger , Davies Robert J. O. , Lee Y. C. Gary , McMichael Andrew J. , Callan Margaret F. C. 
Published: April 2014

Abstract
Human NK cells may be divided into a CD56dim subset and a CD56bright subset. In peripheral blood, CD56dim NK cells dominate, whereas in lymph nodes, CD56bright NK cells are more common. In this study we show that CD56bright NK cells accumulate within inflammatory lesions in a wide variety of clinical diseases affecting several different anatomical sites. We demonstrate that when activated by the monokines IL-12, IL-15, and IL-18, these NK cells promote TNF-α production by CD14+ monocytes in a manner that is dependent on cell:cell contact. Conversely, CD14+ monocytes synergize with monokines to promote IFN-γ production by these NK cells. Again, this interaction is dependent on cell:cell contact. The experiments show that CD56bright NK cells accumulate in inflammatory lesions and, in the appropriate cytokine environment, can engage with CD14+ monocytes in a reciprocal activatory fashion, thereby amplifying the inflammatory response. Such a positive feedback loop is likely to be important in the pathogenesis of chronic inflammatory conditions such as rheumatoid arthritis.
Identification of Selective Basophil Chemoattractants in Human Nasal Polyps as Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor-2
Authors: Hartnell Adele , Heinemann Akos , Conroy Dolores M. , Wait Robin , Sturm Gunter J. , Caversaccio Marco , Jose Peter J. , Williams Timothy J. 
Published: April 2014

AbstractIn a search for novel leukocyte chemoattractants at sites of allergic inflammation, we found basophil-selective chemoattractant activity in extracts of human nasal polyps. The extracts were fractionated by reverse phase HPLC, and the resulting fractions were tested for leukocyte-stimulating activity using sensitive shape change assays. The basophil-selective activity detected was not depleted by a poxvirus CC-chemokine-binding protein affinity column. This activity was further purified by HPLC, and proteins in the bioactive fractions were analyzed by tandem electrospray mass spectrometry. Insulin-like growth factor-2 (IGF-2) was identified in these HPLC fractions, and the basophil-stimulating activity was inhibited by an anti-IGF-2-neutralizing Ab. Recombinant IGF-2 induced a substantial shape change response in basophils, but not eosinophils, neutrophils, or monocytes. IGF-2 stimulated chemokinesis of basophils, but not eosinophils or neutrophils, and synergized with eotaxin-1/CCL11 in basophil chemotaxis. IGF-2 also caused up-regulation of basophil CD11b expression and inhibited apoptosis, but did not stimulate degranulation or Ca2+ flux. Recombinant IGF-1 exhibited similar basophil-selective effects as IGF-2, and both growth factors were detected in nasal polyp extracts by ELISA. This is the first demonstration of chemokinetic factors that increase the motility of basophils, but do not act on other granulocytes or monocytes. IGF-1 and IGF-2 could play a role in the selective recruitment of basophils in vivo.
Decreased Expression of the Ets Family Transcription Factor Fli-1 Markedly Prolongs Survival and Significantly Reduces Renal Disease in MRL/lpr Mice
Authors: Zhang Xian K. , Gallant Sarah , Molano Ivan , Moussa Omar M. , Ruiz Phillip , Spyropoulos Demetri D. , Watson Dennis K. , Gilkeson Gary 
Published: April 2014

Abstract
Increased Fli-1 mRNA is present in PBLs from systemic lupus erythematosus patients, and transgenic overexpression of Fli-1 in normal mice leads to a lupus-like disease. We report in this study that MRL/lpr mice, an animal model of systemic lupus erythematosus, have increased splenic expression of Fli-1 protein compared with BALB/c mice. Using mice with targeted gene disruption, we examined the effect of reduced Fli-1 expression on disease development in MRL/lpr mice. Complete knockout of Fli-1 is lethal in utero. Fli-1 protein expression in heterozygous MRL/lpr (Fli-1+/−) mice was reduced by 50% compared with wild-type MRL/lpr (Fli-1+/+) mice. Fli-1+/− MRL/lpr mice had significantly decreased serum levels of total IgG and anti-dsDNA Abs as disease progressed. Fli-1+/− MRL/lpr mice had significantly increased splenic CD8+ and naive T cells compared with Fli-1+/+ MRL/lpr mice. Both in vivo and in vitro production of MCP-1 were significantly decreased in Fli-1+/− MRL/lpr mice. The Fli-1+/− mice had markedly decreased proteinuria and significantly lower pathologic renal scores. At 48 wk of age, survival was significantly increased in the Fli-1+/− MRL/lpr mice, as 100% of Fli-1+/− MRL/lpr mice were alive, in contrast to only 27% of Fli-1+/+ mice. These findings indicate that Fli-1 expression is important in lupus-like disease development, and that modulation of Fli-1 expression profoundly decreases renal disease and improves survival in MRL/lpr mice.
CD30/CD30 Ligand (CD153) Interaction Regulates CD4+ T Cell-Mediated Graft-versus-Host Disease
Authors: Blazar Bruce R. , Levy Robert B. , Mak Tak W. , Panoskaltsis-Mortari Angela , Muta Hiromi , Jones Monica , Roskos Melinda , Serody Jonathan S. , Yagita Hideo , Podack Eckhard R. , Taylor Patricia A. 
Published: April 2014

AbstractCD30, a TNFR family member, is expressed on activated CD4+ and CD8+ T cells and B cells and is a marker of Hodgkin’s lymphoma; its ligand, CD30L (CD153) is expressed by activated CD4+ and CD8+ T cells, B cells, and macrophages. Signaling via CD30 can lead to proliferation or cell death. CD30-deficient (−/−) mice have impaired thymic negative selection and increased autoreactivity. Although human alloreactive T cells preferentially reside within the CD30+ T cell subset, implicating CD30 as a regulator of T cell immune responses, the role of CD30/CD153 in regulating graft-vs-host disease (GVHD) has not been reported. We used a neutralizing anti-CD153 mAb, CD30−/− donor mice, and generated CD153−/− recipient mice to analyze the effect of CD30/CD153 interaction on GVHD induction. Our data indicate that the CD30/CD153 pathway is a potent regulator of CD4+, but not CD8+, T cell-mediated GVHD. Although blocking CD30/CD153 interactions in vivo did not affect alloreactive CD4+ T cell proliferation or apoptosis, a substantial reduction in donor CD4+ T cell migration into the gastrointestinal tract was readily observed with lesser effects in other GVHD target organs. Blockade of the CD30/CD153 pathway represents a new approach for preventing CD4+ T cell-mediated GVHD.
CD4+CD25bright T Cells in Human Intestinal Lamina Propria as Regulatory Cells
Authors: Makita Shin , Kanai Takanori , Oshima Shigeru , Uraushihara Koji , Totsuka Teruji , Sawada Taisuke , Nakamura Tetsuya , Koganei Kazutaka , Fukushima Tsuneo , Watanabe Mamoru 
Published: April 2014

AbstractIt is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only active suppression by regulatory T cells plays an important role in the normal intestinal homeostasis, but also its dysregulation leads to the development of inflammatory bowel disease. In this study, we demonstrate that the CD4+CD25bright T cells reside in the human intestinal lamina propria (LP) and functionally retain regulatory activities. All human LP CD4+ T cells regardless of CD25 expression constitutively expressed CTLA-4, glucocorticoid-induced TNFR family-related protein, and Foxp3 and proliferate poorly. Although LP CD4+CD25− T cells showed an activated and anergic/memory phenotype, they did not retain regulatory activity. In LP CD4+CD25+ T cells, however, cells expressing CD25 at high levels (CD4+CD25bright) suppressed the proliferation and various cytokine productions of CD4+CD25− T cells. LP CD4+CD25bright T cells by themselves produced fewer amounts of IL-2, IFN-γ, and IL-10. Interestingly, LP CD4+CD25bright T cells with regulatory T activity were significantly increased in patients with active inflammatory bowel disease. These results suggest that CD4+CD25bright T cells found in the normal and inflamed intestinal mucosa selectively inhibit the host immune response and therefore may contribute to the intestinal immune homeostasis.
Proliferation and Differentiation of CD8+ T Cells in the Absence of IL-2/15 Receptor β-Chain Expression or STAT5 Activation
Authors: Teague Ryan M. , Tempero Richard M. , Thomas Sunil , Murali-Krishna Kaja , Nelson Brad H. 
Published: April 2014

AbstractMajor gains in the efficacy of T cell-based therapies for cancer and infectious diseases could be realized through improved understanding of the signals that control expansion and differentiation of CD8+ cytolytic T cells. IL-2, IL-15, and the downstream transcription factor STAT5 have all been implicated as important regulators of these processes, yet there are conflicting data regarding their contribution to in vivo T cell responses. We used a murine adoptive T cell transfer model to examine the contribution of IL-2 and IL-15 signaling to the proliferation and differentiation of naive, CD8+ T cells bearing an OVA-specific TCR transgene (OT-I). OT-I T cells failed to express the high affinity IL-2R (CD25) while proliferating in vivo, irrespective of the mode of Ag delivery. Moreover, OT-I T cells rendered genetically deficient in the shared IL-2/IL-15Rβ subunit (IL-2Rβ) demonstrated normal Ag-induced proliferation and cytolytic activity in vivo. Accordingly, activation of STAT5 was not detected in proliferating IL-2Rβ-deficient OT-I T cells, thus implicating a STAT5-independent cytokine or costimulatory pathway in this process. Even though IL-2 and IL-15 were dispensable for CD8+ T cell proliferation, systemic infusion of IL-2 nevertheless promoted the expansion of OT-I T cells in vivo. Thus, IL-2 and IL-15 signals are not essential for CD8+ T cell proliferation or differentiation, but IL-2 can promote supraphysiological expansion when supplied exogenously. These findings challenge current models that place CD8+ T cell proliferation under the control of STAT5-dependent cytokines and suggest new approaches to the therapeutic manipulation of T cell numbers in vivo.
Functional Analysis of −571 IL-10 Promoter Polymorphism Reveals a Repressor Element Controlled by Sp1
Authors: Steinke John W. , Barekzi Elizabeth , Hagman James , Borish Larry 
Published: April 2014

AbstractTranscriptional dysregulation of the IL-10 gene may contribute to the development and severity of autoimmune, infectious, neoplastic, and allergic diseases. A C to A base substitution has been identified at −571 bp in the IL-10 promoter and has been linked to immune diseases. The role of this polymorphism in IL-10 promoter function was assessed using luciferase reporter constructs. The presence of an A at −571 (A allele) increases promoter activity compared with that of a promoter with a C at this position (C allele). Binding of nuclear extract proteins from IL-10-producing human cell lines to DNA sequences including this base exchange and flanking sequences was demonstrated using EMSAs. Specific binding of the transcription factors Sp1 and Sp3 was demonstrated to a region immediately upstream of the polymorphism. No differences in the binding affinity of recombinant Sp1 were observed between the two forms of the promoter. Reconstitution of Sp1 expression decreased IL-10 promoter function in an Sp1-deficient cell line, demonstrating that this element functions as a repressor. The C to A base exchange relieves the repression mediated by Sp1. Individuals carrying the A allele of the IL-10 promoter may display increased synthesis of IL-10, resulting in suppressed immune responses and a modulation of their susceptibility to autoimmune, infectious, neoplastic, or atopic disease.
The Chemoattractants, IL-8 and Formyl-Methionyl-Leucyl-Phenylalanine, Regulate Granulocyte Colony-Stimulating Factor Signaling by Inducing Suppressor of Cytokine Signaling-1 Expression
Authors: Stevenson Nigel J. , Haan Serge , McClurg Angela E. , McGrattan Michael J. , Armstrong Marilyn A. , Heinrich Peter C. , Johnston James A. 
Published: April 2014

AbstractSuppressors of cytokine signaling (SOCS) are encoded by immediate early genes known to inhibit cytokine responses in a classical feedback loop. SOCS gene expression has been shown to be induced by many cytokines, growth factors, and innate immune stimuli, such as LPS. In this paper, we report that the chemoattractants, IL-8 and fMLP, up-regulate SOCS1 mRNA in human myeloid cells, primary human neutrophils, PBMCs, and dendritic cells. fMLP rapidly up-regulates SOCS1, whereas the induction of SOCS1 upon IL-8 treatment is delayed. IL-8 and fMLP did not signal via Jak/STATs in primary human macrophages, thus implicating the induction of SOCS by other intracellular pathways. As chemoattractant-induced SOCS1 expression in neutrophils may play an important role in regulating the subsequent response to growth promoting cytokines like G-CSF, we investigated the effect of chemoattractant-induced SOCS1 on cytokine signal transduction. We show that pretreatment of primary human neutrophils with fMLP or IL-8 blocks G-CSF-mediated STAT3 activation. This study provides evidence for cross-talk between chemoattractant and cytokine signal transduction pathways involving SOCS proteins, suggesting that these chemotactic factors may desensitize neutrophils to G-CSF via rapid induction of SOCS1 expression.
Rates of Recombination and Chain Pair Biases Greatly Influence the Primary γδ TCR Repertoire in the Thymus of Adult Mice
Authors: Pereira Pablo , Boucontet Laurent 
Published: April 2014

AbstractAnalyses of the rearrangement status of the TCRγ and TCRδ chain loci in progenies of individual γδ thymocytes showed a hierarchy of the different Vγ and Vδ gene segments to participate in a recombination reaction. Moreover, individual TCRγ chains only pair efficiently with a variable number of TCRδ chains. Interestingly, these two parameters are inversely correlated such that the TCRγ and TCRδ chains that rearrange more often show a higher level of restriction in their pairing capabilities. Our data suggest that these mechanisms, together with a natural variation affecting the expected frequencies at which rearrangement of different Vγ gene segments give raise to functional TCRγ chains, have coevolved to maximize the diversity of the γδ TCR repertoire minimizing the risk that a γδ T cell will express more than one TCR specificity at the cell surface, despite the fact that multiple TCRγ rearrangements take place in the same progenitor cell.
Signaling of Apoptosis through TLRs Critically Involves Toll/IL-1 Receptor Domain-Containing Adapter Inducing IFN-β, but Not MyD88, in Bacteria-Infected Murine Macrophages
Authors: Ruckdeschel Klaus , Pfaffinger Gudrun , Haase Rudolf , Sing Andreas , Weighardt Heike , Häcker Georg , Holzmann Bernhard , Heesemann Jürgen 
Published: April 2014

Abstract
TLRs are important sensors of the innate immune system that serve to identify conserved microbial components to mount a protective immune response. They furthermore control the survival of the challenged cell by governing the induction of pro- and antiapoptotic signaling pathways. Pathogenic Yersinia spp. uncouple the balance of life and death signals in infected macrophages, which compels the macrophage to undergo apoptosis. The initiation of apoptosis by Yersinia infection specifically involves TLR4 signaling, although Yersinia can activate TLR2 and TLR4. In this study we characterized the roles of downstream TLR adapter proteins in the induction of TLR-responsive apoptosis. Experiments using murine macrophages defective for MyD88 or Toll/IL-1R domain-containing adapter inducing IFN-β (TRIF) revealed that deficiency of TRIF, but not of MyD88, provides protection against Yersinia-mediated cell death. Similarly, apoptosis provoked by treatment of macrophages with the TLR4 agonist LPS in the presence of a proteasome inhibitor was inhibited in TRIF-defective, but not in MyD88-negative, cells. The transfection of macrophages with TRIF furthermore potently promoted macrophage apoptosis, a process that involved activation of a Fas-associated death domain- and caspase-8-dependent apoptotic pathway. These data indicate a crucial function of TRIF as proapoptotic signal transducer in bacteria-infected murine macrophages, an activity that is not prominent for MyD88. The ability to elicit TRIF-dependent apoptosis was not restricted to TLR4 activation, but was also demonstrated for TLR3 agonists. Together, these results argue for a specific proapoptotic activity of TRIF as part of the host innate immune response to bacterial or viral infection.
NK Cells Use Perforin Rather than Granulysin for Anticryptococcal Activity
Authors: Ma Ling Ling , Wang Christopher L. C. , Neely Graham G. , Epelman Slava , Krensky Alan M. , Mody Christopher H. 
Published: April 2014

Abstract
Cytotoxic lymphocytes have the capacity to kill microbes directly; however, the mechanisms involved are poorly understood. Using Cryptococcus neoformans, which causes a potentially fatal fungal infection in HIV-infected patients, our previous studies showed that granulysin is necessary, while perforin is dispensable, for CD8 T lymphocyte fungal killing. By contrast, the mechanisms by which NK cells exert their antimicrobial activity are not clear, and in particular, the contribution of granulysin and perforin to NK-mediated antifungal activity is unknown. Primary human NK cells and a human NK cell line YT were found to constitutively express granulysin and perforin, and possessed anticryptococcal activity, in contrast to CD8 T lymphocytes, which required stimulation. When granulysin protein and mRNA were blocked by granulysin small interfering RNA, the NK cell-mediated antifungal effect was not affected in contrast to the abrogated activity observed in CD8 T lymphocytes. However, when perforin was inhibited by concanamycin A, and silenced using hairpin small interfering RNA, the anticryptococcal activities of NK cells were abrogated. Furthermore, when granulysin and perforin were both inhibited, the anticryptococcal activities of the NK cells were not reduced further than by silencing perforin alone. These results indicate that the antifungal activity is constitutively expressed in NK cells in contrast to CD8 T lymphocytes, in which it requires prior activation, and perforin, but not granulysin, plays the dominant role in NK cell anticryptococcal activity, in contrast to CD8 T lymphocytes, in which granulysin, but not perforin, plays the dominant role in anticryptococcal activity.
Inhibition of the Growth ofToxoplasma gondiiin Immature Human Dendritic Cells Is Dependent on the Expression of TNF-α Receptor 2
Authors: Giese Anja , Stuhlsatz Silke , Däubener Walter , MacKenzie Colin R. 
Published: April 2014

AbstractAn effective immunity to Toxoplasma gondii in humans is dependent on the cellular immune response. Toxoplasma can infect and replicate in almost all nucleated cells, and the most important cytokine regulating the growth in humans is IFN-γ; however, the role of TNF-α has to date been largely described to be synergistic. We show that, compared with mature human dendritic cells (mDC), immature human DC (iDC) demonstrate a reduced parasite proliferation when infected with Toxoplasma. This toxoplasmostasis was only present in iDC after 11 days of culture and was not present in DC that had been matured ex vivo using a cytokine mixture (mDC). Spontaneous toxoplasmostatic activity has previously only been described in fresh human monocytes, and the mechanism involved is as yet unclear. We show that, in comparison with an absence of expression in mDC, TNF-R2 is expressed in both iDC and monocytes infected with Toxoplasma, and furthermore, that blocking the TNF-R2 with Abs abrogates the toxoplasmostasis in the iDC. These findings demonstrate a functional role for TNF-R2 in the newly described spontaneous toxoplasmostasis of iDC.