bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Essential Involvement of Cross-Talk between IFN-γ and TGF-β in the Skin Wound-Healing Process
Authors: Ishida Yuko , Kondo Toshikazu , Takayasu Tatsunori , Iwakura Yoichiro , Mukaida Naofumi 
Published: April 2014

Abstract
Several lines of in vitro evidence suggest the potential role of IFN-γ in angiogenesis and collagen deposition, two crucial steps in the wound healing process. In this report, we examined the role of IFN-γ in the skin wound healing process utilizing WT and IFN-γ KO mice. In WT mice, excisional wounding induced IFN-γ mRNA and protein expression by infiltrating macrophages and T cells, with a concomitant enhancement of IL-12 and IL-18 gene expression. Compared with WT mice, IFN-γ KO mice exhibited an accelerated wound healing as evidenced by rapid wound closure and granulation tissue formation. Moreover, IFN-γ KO mice exhibited enhanced angiogenesis with augmented vascular endothelial growth factor mRNA expression in wound sites, compared with WT mice, despite a reduction in the infiltrating neutrophils, macrophages, and T cells. IFN-γ KO mice also exhibited accelerated collagen deposition with enhanced production of TGF-β1 protein in wound sites, compared with WT mice. Furthermore, the absence of IFN-γ augmented the TGF-β1-mediated signaling pathway, as evidenced by increases in the levels of total and phosphorylated Smad2 and a reciprocal decrease in the levels of Smad7. These results demonstrate that there is crosstalk between the IFN-γ/Stat1 and TGF-β1/Smad signaling pathways in the wound healing process.
A Molecular Defect in Intracellular Lipid Signaling in Human Neutrophils in Localized Aggressive Periodontal Tissue Damage
Authors: Gronert Karsten , Kantarci Alpdogan , Levy Bruce D. , Clish Clary B. , Odparlik Sabine , Hasturk Hatice , Badwey John A. , Colgan Sean P. , Van Dyke Thomas E. , Serhan Charles N. 
Published: April 2014

Abstract
Host defense mechanisms are impaired in patients with congenital neutrophil (polymorphonuclear neutrophils (PMN)) defects. Impaired PMN chemotaxis is observed in localized aggressive periodontitis (LAP), a familial disorder characterized by destruction of the supporting structures of dentition. In the present studies, we sought evidence for molecular events underlying this aberrant human PMN phenotype. To this end, PMN transendothelial migration and superoxide anion generation were assessed with LAP patients and asymptomatic family members, as well as patients with other chronic mucosal inflammation. PMN from LAP patients showed decreased transmigration across vascular endothelial monolayers (18 ± 12% of control, n = 4) and increased superoxide anion generation (358 ± 37%, p = 0.003). Gene expression was analyzed using oligonucleotide microarrays and fluorescence-based kinetic PCR. cDNA microarray and kinetic-PCR analysis revealed diminished RNA expression of leukocyte-type diacylglycerol (DAG) kinase α in PMN from LAP patients (4.6 ± 1.7 relative units, n = 6, p = 0.007) compared with asymptomatic individuals (51 ± 27 relative units, n = 7). DAG kinase activity was monitored by DAG phosphorylation and individual DAG molecular species were quantified using liquid chromatography and tandem mass spectrometry-based lipidomics. DAG kinase activity was also significantly decreased (73 ± 2%, p = 0.007) and correlated with increased accumulation of 1,2-diacyl-sn-3-glycerol substrates (p = 0.01). These results implicate defects in both PMN transendothelial migration and PMN DAG kinase α signaling as disordered functions in LAP. Moreover, they identify a potential molecular lesion in PMN signal transduction that may account for their aberrant responses and tissue destruction in this disease.
Expression of CD154 (CD40 Ligand) by Human Lung Fibroblasts: Differential Regulation by IFN-γ and IL-13, and Implications for Fibrosis
Authors: Kaufman Julia , Sime Patricia J. , Phipps Richard P. 
Published: April 2014

AbstractThe CD40-CD40 ligand (CD40L) system (CD154) is a central means of immune cell communication crucial for Ig class switching and enhanced Ag presentation. CD40 is also a key signaling conduit to activate nonhematopoietic cells, such as fibroblasts and endothelial cells, to produce proinflammatory mediators. Disruption of the CD40-CD40L pathway reduces lung inflammation and fibrosis, autoimmune disease and atherosclerosis. Non-bone marrow-derived structural cells are not known to express CD40L. In this study, we reveal the intriguing finding that primary strains of human lung fibroblasts derived from normal and scarred lung express both CD40L mRNA and protein. Interestingly, CD40L expression is down-regulated by IFN-γ, a type 1 cytokine with antiscarring properties, and is up-regulated by the profibrogenic type 2 cytokine IL-13. Flow cytometry and laser confocal microscopy revealed that the majority of CD40L was located intracellularly. Importantly, fibroblast strains from human idiopathic pulmonary fibrosis tissue expressed increased levels of CD40L compared with fibroblasts from nonscarred lung. Fibroblasts in the scarred areas of human lung tissue expressed high levels of CD40L. Finally, the blood and lung lavage levels of CD40L are significantly elevated in fibrosis patients compared with normals. These new findings demonstrate that fibroblasts are a new source of CD40L and that those involved in scarring may have undergone a selected expansion for high CD40L expression. Moreover, the antifibrotic activity of IFN-γ may involve the down-regulation of fibroblast CD40L levels. We speculate that fibroblast-derived CD40L plays a role in promoting fibroblast activation and possibly in interaction with CD40 bearing cells.
The C10/CCL6 Chemokine and CCR1 Play Critical Roles in the Pathogenesis of IL-13-Induced Inflammation and Remodeling
Authors: Ma Bing , Zhu Zhou , Homer Robert J. , Gerard Craig , Strieter Robert , Elias Jack A. 
Published: April 2014

AbstractIL-13 is a potent stimulator of inflammation and tissue remodeling that plays a key role in the pathogenesis of a wide variety of human disorders. To further understand these responses, studies were undertaken to define the role(s) of the chemokine C10/CCL6 in the pathogenesis of IL-13-induced alterations in the murine lung. IL-13 was a very potent stimulator of C10/CCL6 mRNA and protein, and IL-13-induced inflammation, alveolar remodeling, and compliance alterations were markedly ameliorated after C10/CCL6 neutralization. Treatment with anti-C10/CCL6 decreased the levels of mRNA encoding matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of metalloproteinase-4 (TIMP-4) in lungs from wild-type mice. C10/CCL6 neutralization also decreased the ability of IL-13 to stimulate the production of monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, MMP-2, MMP-9, and cathepsins-K, -L, and -S and the ability of IL-13 to inhibit α1-antitrypsin. In accord with these findings, a targeted null mutation of CCR1, a putative C10/CCL6 receptor, also decreased IL-13-induced inflammation and alveolar remodeling and caused alterations in chemokines, proteases, and antiproteases comparable to those seen after C10/CCL6 neutralization. These C10/CCL6 and CCR1 manipulations did not alter the production of transgenic IL-13. These studies demonstrate that IL-13 is a potent stimulator of C10/CCL6 and highlight the importance of C10/CCL6 and signaling via CCR1 in the pathogenesis of the IL-13-induced pulmonary phenotype. They also describe a C10/CCL6 target gene cascade in which C10/CCL6 induction is required for optimal IL-13 stimulation of selected chemokines (monocyte chemoattractant protein-1 and MIP-1α) and proteases (MMP-2, MMP-9, and cathepsins-K, -L, and -S) and the inhibition of α1-antitrypsin.
Chemotaxis and Calcium Responses of Phagocytes to Formyl Peptide Receptor Ligands Is Differentially Regulated by Cyclic ADP Ribose
Authors: Partida-Sánchez Santiago , Iribarren Pablo , Moreno-García Miguel E. , Gao Ji-Liang , Murphy Philip M. , Oppenheimer Norman , Wang Ji Ming , Lund Frances E. 
Published: April 2014

AbstractCyclic ADP ribose (cADPR) is a calcium-mobilizing metabolite that regulates intracellular calcium release and extracellular calcium influx. Although the role of cADPR in modulating calcium mobilization has been extensively examined, its potential role in regulating immunologic responses is less well understood. We previously reported that cADPR, produced by the ADP-ribosyl cyclase, CD38, controls calcium influx and chemotaxis of murine neutrophils responding to fMLF, a peptide agonist for two chemoattractant receptor subtypes, formyl peptide receptor and formyl peptide receptor-like 1. In this study, we examine whether cADPR is required for chemotaxis of human monocytes and neutrophils to a diverse array of chemoattractants. We found that a cADPR antagonist and a CD38 substrate analogue inhibited the chemotaxis of human phagocytic cells to a number of formyl peptide receptor-like 1-specific ligands but had no effect on the chemotactic response of these cells to ligands selective for formyl peptide receptor. In addition, we show that the cADPR antagonist blocks the chemotaxis of human monocytes to CXCR4, CCR1, and CCR5 ligands. In all cases, we found that cADPR modulates intracellular free calcium levels in cells activated by chemokines that induce extracellular calcium influx in the apparent absence of significant intracellular calcium release. Thus, cADPR regulates calcium signaling of a discrete subset of chemoattractant receptors expressed by human leukocytes. Since many of the chemoattractant receptors regulated by cADPR bind to ligands that are associated with clinical pathology, cADPR and CD38 represent novel drug targets with potential application in chronic inflammatory and neurodegenerative disease.
Lymphoid Hyperplasia Resulting in Immune Dysregulation Is Caused by Porcine Reproductive and Respiratory Syndrome Virus Infection in Neonatal Pigs
Authors: Lemke Caitlin D. , Haynes Joseph S. , Spaete Rodger , Adolphson Deb , Vorwald Ann , Lager Kelly , Butler John E. 
Published: April 2014

AbstractAmid growing evidence that numerous viral infections can produce immunopathology, including nonspecific polyclonal lymphocyte activation, the need to test the direct impact of an infecting virus on the immune system of the host is crucial. This can best be tested in the isolator piglet model in which maternal and other extrinsic influences can be excluded. Therefore, neonatal isolator piglets were colonized with a benign Escherichia coli, or kept germfree, and then inoculated with wild-type porcine reproductive and respiratory syndrome virus (PRRSV) or sham medium. Two weeks after inoculation, serum IgM, IgG, and IgA levels were 30- to 50-, 20- to 80-, and 10- to 20-fold higher, respectively, in animals receiving virus vs sham controls, although &lt;1% was virus specific. PRRSV-infected piglets also had bronchial tree-associated lymph nodes and submandibular lymph nodes that were 5–10 times larger than colonized, sham-inoculated animals. Size-exclusion fast performance liquid chromatography revealed that PRRSV-infected sera contained high-molecular-mass fractions that contained IgG, suggesting the presence of immune complexes. Lesions, inflammatory cell infiltration, glomerular deposits of IgG, IgM, and IgA, and Abs of all three isotypes to basement membrane and vascular endothelium were observed in the kidneys of PRRSV-infected piglets. Furthermore, autoantibodies specific for Golgi Ags and dsDNA could be detected 3–4 wk after viral inoculation. These data demonstrate that PRRSV induces B cell hyperplasia in isolator piglets that leads to immunologic injury and suggests that the isolator piglet model could serve as a useful model to determine the mechanisms of virus-induced immunopathology in this species.
Human Thymus Exports Naive CD8 T Cells That Can Home to Nonlymphoid Tissues
Authors: Zippelius Alfred , Bioley Gilles , Le Gal Frédérique-Anne , Rufer Nathalie , Brandes Marlene , Batard Pascal , De Smedt Magda , Plum Jean , Speiser Daniel E. , Cerottini Jean-Charles , Dietrich Pierre-Yves , Romero Pedro , Pittet Mikaël J. 
Published: April 2014

Abstract
Functionally naive CD8 T cells in peripheral blood from adult humans can be fully described by their CD45RAbrightCCR7+CD62L+ cell surface phenotype. Cord blood lymphocytes, from healthy newborns, are homogenously functionally naive. Accordingly, the majority of cord blood CD8 T cells express the same pattern of cell surface molecules. Unexpectedly, however, a significant fraction of cord blood CD8 T cells express neither CCR7 nor CD62L. Yet these cells remain functionally naive as they contain high levels of TCR excision circles, have long telomeres, display highly polyclonal TCRs, and do not exhibit immediate effector functions. In addition, these CD8 T cells already represent a significant fraction of the mature naive CD8 single-positive thymocyte repertoire and may selectively express the cutaneous lymphocyte Ag. We suggest that CD8 single-positive thymocytes comprise two pools of naive precursors that exhibit distinct homing properties. Once seeded in the periphery, naive CCR7+CD62L+ CD8 T cells patrol secondary lymphoid organs, whereas naive CCR7−CD62L− CD8 T cells selectively migrate to peripheral tissues such as skin.
The Centromeric Region of Chromosome 7 from MRL Mice (Lmb3) Is an Epistatic Modifier of Fas for Autoimmune Disease Expression
Authors: Kong Philip L. , Morel Laurence , Croker Byron P. , Craft Joseph 
Published: April 2014

Abstract
Lupus is a prototypic systemic autoimmune disease that has a significant genetic component in its etiology. Several genome-wide screens have identified multiple loci that contribute to disease susceptibility in lupus-prone mice, including the Fas-deficient MRL/Faslpr strain, with each locus contributing in a threshold liability manner. The centromeric region of chromosome 7 was identified as a lupus susceptibility locus in MRL/Faslpr mice as Lmb3. This locus was backcrossed onto the resistant C57BL/6 (B6) background, in the presence or absence of Fas, resulting in the generation of B6.MRLc7 congenic animals. Detailed analysis of these animals showed that Lmb3 enhances and accelerates several characteristics of lupus, including autoantibody production, kidney disease, and T cell activation, as well as accumulation of CD4−CD8− double-negative T cells, the latter a feature of Fas-deficient mice. These effects appeared to be dependent on the interaction between Lmb3 and Fas deficiency, as Lmb3 on the B6/+Fas-lpr background did not augment any of the lupus traits measured. These findings confirm the role of Lmb3 in lupus susceptibility, as a modifier of Faslpr phenotype, and illustrate the importance of epistatic interaction between genetic loci in the etiology of lupus. Furthermore, they suggest that the genetic lesion(s) in MRLc7 is probably different from those in NZMc7 (Sle3/5), despite a significant overlap of these two intervals.
Transgenic Expression of Insulin Receptor Substrate 2 in Murine B Cells Alters the Cell Density-Dependence of IgE Production In Vitro and Enhances IgE Production In Vivo
Authors: Kelly-Welch Ann E. , Wang Helen Y. , Wang Ling-Mei , Pierce Jacalyn H. , Jay Gilbert , Finkelman Fred , Keegan Achsah D. 
Published: April 2014

Abstract
Previous studies have shown that insulin receptor substrate (IRS)1 and IRS2 mediate proliferative and antiapoptotic signaling through the IL-4R in 32D cells; however their role in regulating normal B cell responses is not clear. To investigate the role of IRS2 in normal B cell function, we developed IRS2 transgenic (Tg) mice on the C57BL/6 background. Western blot analysis revealed a 2-fold elevation in IRS2 protein levels in Tg+ mice compared with littermate controls and a 3-fold increase in basal tyrosine phosphorylated IRS2 in the absence of IL-4 stimulation. IL-4-induced tyrosine phosphorylation of IRS2 was elevated in Tg+ B cells, whereas IL-4-induced phosphorylation of STAT6 was similar between Tg+ and Tg− B cells. Tg expression of IRS2 had little effect on IL-4-mediated proliferation and no effect on protection from apoptosis. However, production of IgE and IgG1 by Tg+ B cells using standard in vitro conditions was diminished 50–60%. Because Ig production in vitro is known to be highly cell concentration-dependent, we performed experiments at different cell concentrations. Interestingly, at very low B cell concentrations (1000–5000 B cells/well), IgE and IgG1 production by Tg+ B cells was greater than that of controls, whereas at higher cell concentrations (10,000–20,000 cells/well) Ig production by Tg+ B cells was less than controls. Furthermore, in vivo immunization with OVA-alum or goat anti-IgD resulted in elevated serum IgE levels in the Tg+ mice. These results indicate that overexpression of IRS2 alters the B cell intrinsic density-dependence of IgE and IgG1 production in vitro and enhances IgE responses in vivo.
Circadian Rhythms of Granzyme B, Perforin, IFN-γ, and NK Cell Cytolytic Activity in the Spleen: Effects of Chronic Ethanol
Authors: Arjona Alvaro , Boyadjieva Nadka , Sarkar Dipak K. 
Published: April 2014

Abstract
Recent studies show that alterations in the body’s biological rhythms can lead to serious pathologies, including cancer. Acute and chronic ethanol consumption impairs the immune system by causing specific defects in the cellular components of the innate immune response and by creating increased risk and susceptibility to infections and cancer. NK cells are critical for immune surveillance against infected and malignant cells. To assess whether NK cell function follows a circadian trend and to determine ethanol effects on this rhythm, we measured, over a 24-h period, mRNA and protein levels of granzyme B, perforin, and the cytokine IFN-γ, as well as NK cell activity, in the splenocytes of ad libitum-fed, pair-fed, and ethanol-fed Sprague Dawley male rats. Circadian rhythms were found in mRNA and protein levels of granzyme B, perforin, and IFN-γ. A circadian pattern was also detected in NK cell cytolytic activity. Our data further demonstrated how chronic ethanol suppressed NK cell activity by directly disrupting the circadian rhythms of granzyme B, perforin, and IFN-γ. These findings identify the circadian functions of splenic NK cells and show the vulnerability of these rhythms to chronic ethanol.
IL-12 Priming during In Vitro Antigenic Stimulation Changes Properties of CD8 T Cells and Increases Generation of Effector and Memory Cells
Authors: Chang Jun , Cho Jae-Ho , Lee Seung-Woo , Choi So-Young , Ha Sang-Jun , Sung Young-Chul 
Published: April 2014

Abstract
Antigenic and costimulatory signals trigger a developmental program by which naive CD8 T cells differentiate into effector and memory cells. However, initial cytokine signals that regulate the generation of effector and memory CD8 T cells are not well understood. In this study, we show that IL-12 priming during in vitro antigenic stimulation results in the significant increase of both primary and memory CD8 T cell population in mice after adoptive transfer of activated cells. The effect of IL-12 priming is closely associated with qualitative changes in CD8 T cells, such as reduced MHC I tetramer binding and CD69 expression, altered distribution of lipid rafts, decreased cytolytic activity, and less susceptibility to apoptosis. Furthermore, exogenous IL-12 priming improved the intrinsic survival properties of memory CD8 T cells, leading to better protective immunity and vaccine-induced memory CD8 T cell responses. However, the experiments with IL-12p40- and IL-12Rβ1-deficient mice showed similar levels of primary and memory CD8 T cell responses compared with wild-type mice, implying that endogenous IL-12 and/or IL-12R signaling in vivo is not critical for CD8 T cell immunity. Together, our results suggest that IL-12 can serve as an important, but dispensable regulatory factor for the development of CD8 T cells, and IL-12 priming could be useful in many medical applications.
Compromised Humoral and Delayed-Type Hypersensitivity Responses in IL-23-Deficient Mice
Authors: Ghilardi Nico , Kljavin Noelyn , Chen Qi , Lucas Sophie , Gurney Austin L. , de Sauvage Frederic J. 
Published: April 2014

Abstract
The heterodimeric cytokine IL-23 consists of a private cytokine-like p19 subunit and a cytokine receptor-like subunit, p40, which is shared with IL-12. Previously reported IL-12p40-deficient mice have profound immune defects resulting from combined deficiency in both IL-12 and IL-23. To address the effects of specific IL-23 deficiency, we generated mice lacking p19 by gene targeting. These mice display no overt abnormalities but mount severely compromised T-dependent humoral immune responses. IL-23p19−/− mice produce strongly reduced levels of Ag-specific Igs of all isotypes, but mount normal T-independent B cell responses. In addition, delayed type hypersensitivity responses are strongly impaired in the absence of IL-23, indicating a defect at the level of memory T cells. T cells stimulated with IL-23-deficient APCs secrete significantly reduced amounts of the proinflammatory cytokine IL-17, and IL-23-deficient mice phenotypically resemble IL-17-deficient animals. Thus, IL-23 plays a critical role in T cell-dependent immune responses, and our data provide further support for the existence of an IL-23/IL-17 axis of communication between the adaptive and innate parts of the immune system.
CD4 T Cell-Dependent CD8 T Cell Maturation
Authors: Khanolkar Aaruni , Fuller Michael J. , Zajac Allan J. 
Published: April 2014

Abstract
We have investigated the contribution of CD4 T cells to the optimal priming of functionally robust memory CD8 T cell subsets. Intranasal infection of CD4 T cell-deficient (CD4−/−) mice with lymphocytic choriomeningitis virus resulted in the elaboration of virus-specific CD8 T cell responses that cleared the infection. However, by comparison with normal mice, the virus-specific CD8 T cells in CD4−/− mice were quantitatively and qualitatively different. In normal mice, lymphocytic choriomeningitis virus-specific memory CD8 T cells are CD44high, many are CD122high, and a majority of these cells regain expression of CD62L overtime. These cells produce IFN-γ and TNF-α, and a subset also produces IL-2. In the absence of CD4 T cell help, a distinct subset of memory CD8 T cells develops that remains CD62Llow up to 1 year after infection and exhibits a CD44intCD122low phenotype. These cells are qualitatively different from their counterparts in normal hosts, as their capacity to produce TNF-α and IL-2 is diminished. In addition, although CD4-independent CD8 T cells can contain the infection following secondary viral challenge, their ability to expand is impaired. These findings suggest that CD4 T cell responses not only contribute to the optimal priming of CD8 T cells in chronically infected hosts, but are also critical for the phenotypic and functional maturation of CD8 T cell responses to Ags that are more rapidly cleared. Moreover, these data imply that the development of CD62Lhigh central memory CD8 T cells is arrested in the absence of CD4 T cell help.