bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ig-Like Transcript 2 (ILT2)/Leukocyte Ig-Like Receptor 1 (LIR1) Inhibits TCR Signaling and Actin Cytoskeleton Reorganization
Authors: Dietrich Jes , Cella Marina , Colonna Marco 
Published: April 2014

Abstract
Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) is a receptor, specific for MHC class I molecules, that inhibits lymphoid and myeloid cells. Here, we analyzed the molecular and cellular mechanisms by which ILT2 modulates T cell activation in primary CTLs and transfected T cell lines. We found that cross-linking with the TCR and the activity of Src tyrosine kinase p56lck were required for phosphorylation of ILT2 and subsequent recruitment of Src homology protein 1. In contrast, ILT2 triggering resulted in reduced phosphorylation of TCRζ and linker for activation of T cells, which led to reduced TCRζ-ZAP70 complex formation, as well as extracellular signal-related kinase 1 and 2 activation. Furthermore, ILT2 inhibited both superantigen and anti-TCR Ab-induced rearrangement of the actin cytoskeleton. The inhibitory effect mediated by ILT2 is probably concentrated at the APC-T cell interface because both TCR and ILT2 were strongly polarized toward the APC upon engagement by their specific ligands. Thus, ILT2 inhibits both signaling and cellular events involved in the activation of T cells.
Mycoplasma fermentansLipoprotein M161Ag-Induced Cell Activation Is Mediated by Toll-Like Receptor 2: Role of N-Terminal Hydrophobic Portion in its Multiple Functions
Authors: Nishiguchi Miyuki , Matsumoto Misako , Takao Toshifumi , Hoshino Masaru , Shimonishi Yasutsugu , Tsuji Shoutaro , Begum Nasim A. , Takeuchi Osamu , Akira Shizuo , Toyoshima Kumao , Seya Tsukasa 
Published: April 2014

AbstractM161Ag is a 43-kDa surface lipoprotein of Mycoplasma fermentans, serving as a potent cytokine inducer for monocytes/macrophages, maturing dendritic cells (DCs), and activating host complement on affected cells. It possesses a unique N-terminal lipo-amino acid, S-diacylglyceryl cysteine. The 2-kDa macrophage-activating lipopeptide-2 (MALP-2), recently identified as a ligand for Toll-like receptor 2 (TLR2), is derived from M161Ag. In this study, we identified structural motifs sustaining the functions of M161Ag using wild-type and unlipidated rM161Ag with (SP+) or without signal peptides (SP−). Because the SP+ rM161Ag formed dimers via 25Cys, we obtained a monomeric form by mutagenesis (SP+C25S). Only wild type accelerated maturation of human DCs as determined by the CD83/86 criteria, suggesting the importance of the N-terminal fatty acids for this function. Wild-type and the SP+ form of monomer induced secretion of TNF-α and IL-12 p40 by human monocytes and DCs. Either lipid or signal peptide at the N-terminal portion of monomer was required for expression of this function. In contrast, murine macrophages produced TNF-α in response to wild type, but not to any recombinant form of M161Ag, suggesting the species-dependent response to rM161Ag. Wild-type and both monomeric and dimeric SP+ forms possessed the ability to activate complement via the alternative pathway. Again, the hydrophobic portion was associated with this function. These results, together with the finding that macrophages from TLR2-deficient mice did not produce TNF-α in response to M161Ag, infer that the N-terminal hydrophobic structure of M161Ag is important for TLR2-mediated cell activation and complement activation.
Antagonists of Calcium Fluxes and Calmodulin Block Activation of the p21-Activated Protein Kinases in Neutrophils
Authors: Lian Jian P. , Crossley Lisa , Zhan Qian , Huang Riyun , Coffer Paul , Toker Alex , Robinson Dwight , Badwey John A. 
Published: April 2014

Abstract
Neutrophils stimulated with fMLP or a variety of other chemoattractants that bind to serpentine receptors coupled to heterotrimeric G proteins exhibit rapid activation of two p21-activated protein kinases (Paks) with molecular masses of ∼63 and 69 kDa (γ- and α-Pak). Previous studies have shown that products of phosphatidylinositol 3-kinase and tyrosine kinases are required for the activation of Paks. We now report that a variety of structurally distinct compounds which interrupt different stages in calcium/calmodulin (CaM) signaling block activation of the 63- and 69-kDa Paks in fMLP-stimulated neutrophils. These antagonists included selective inhibitors of phospholipase C (1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione), the intracellular Ca2+ channel (8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate), CaM (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; N-(4-aminobutyl)-5-chloro-1-naphthalenesulfonamide; trifluoperazine), and CaM-activated protein kinases (N-[2-(N-(chlorocinnamyl)-N-methylaminomethyl)phenyl]-N-[2-hydroxyethyl]-4-methoxybenzenesulfonamide). This inhibition was dose-dependent with IC50 values very similar to those that interrupt CaM-dependent reactions in vitro. In contrast, less active analogues of these compounds (1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-2,5-pyrrolidinedione; N-(6-aminohexyl)-1-naphthalenesulfonamide; N-(4-aminobutyl)-1-naphthalenesulfonamide; promethazine; 2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzyl-amine]) did not affect activation of Paks in these cells. CaM antagonists (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; trifluoperazine), but not their less-active analogues (N-(6-aminohexyl)-1-naphthalenesulfonamide; promethazine), were also found to block activation of the small GTPases Ras and Rac in stimulated neutrophils along with the extracellular signal-regulated kinases. These data strongly suggest that the Ca2+/CaM complex plays a major role in the activation of a number of enzyme systems in neutrophils that are regulated by small GTPases.
Lipopolysaccharide-Induced IL-18 Secretion from Murine Kupffer Cells Independently of Myeloid Differentiation Factor 88 That Is Critically Involved in Induction of Production of IL-12 and IL-1β
Authors: Seki Ekihiro , Tsutsui Hiroko , Nakano Hiroki , Tsuji Noriko M. , Hoshino Katsuaki , Adachi Osamu , Adachi Keishi , Futatsugi Shizue , Kuida Keisuke , Takeuchi Osamu , Okamura Haruki , Fujimoto Jiro , Akira Shizuo , Nakanishi Kenji 
Published: April 2014

AbstractIL-18, produced as biologically inactive precursor, is secreted from LPS-stimulated macrophages after cleavage by caspase-1. In this study, we investigated the mechanism underlying caspase-1-mediated IL-18 secretion. Kupffer cells constantly stored IL-18 and constitutively expressed caspase-1. Inhibition of new protein synthesis only slightly reduced IL-18 secretion, while it decreased and abrogated their IL-1β and IL-12 secretion, respectively. Kupffer cells deficient in Toll-like receptor (TLR) 4, an LPS-signaling receptor, did not secrete IL-18, IL-1β, and IL-12 upon LPS stimulation. In contrast, Kupffer cells lacking myeloid differentiation factor 88 (MyD88), an adaptor molecule for TLR-mediated-signaling, secreted IL-18 without IL-1β and IL-12 production in a caspase-1-dependent and de novo synthesis-independent manner. These results indicate that MyD88 is essential for IL-12 and IL-1β production from Kupffer cells while their IL-18 secretion is mediated via activation of endogenous caspase-1 without de novo protein synthesis in a MyD88-independent fashion after stimulation with LPS. In addition, infection with Listeria monocytogenes, products of which have the capacity to activate TLR, increased serum levels of IL-18 in wild-type and MyD88-deficient mice but not in caspase-1-deficient mice, whereas it induced elevation of serum levels of IL-12 in both wild-type and caspase-1-deficient mice but not in MyD88-deficient mice. Taken together, these results suggested caspase-1-dependent, MyD88-independent IL-18 release in bacterial infection.
A Role for IFN-αβ in Virus Infection-Induced Sensitization to Endotoxin
Authors: Doughty Lesley A. , Nguyen Khuong B. , Durbin Joan E. , Biron Christine A. 
Published: April 2014

Abstract
Underlying viral infections can heighten sensitivity and worsen cytokine-mediated disease following secondary inflammatory challenges. Mechanisms for this are poorly understood. The impact of the innate response to lymphocytic choriomeningitis virus (LCMV) infection on sensitivity to endotoxin (LPS) was investigated. Compared with uninfected mice, infection with LCMV for 2-days-sensitized mice to LPS by ∼2-fold for lethality and by 2- to 6-fold for serum TNF-α levels. Priming for LPS-induced TNF-α was also seen with splenic and peritoneal leukocytes isolated from infected mice and challenged with LPS ex vivo. The effect on TNF-α production was present in the absence of IFN-γ, its major producers NK and T cells, and the major pathways for its induction through IL-12 and the signal transducer and activator of transcription 4 (STAT4), and therefore was IFN-γ independent. Early LCMV infection induces high concentrations of the type 1 IFNs, IFN-αβ. Administration of recombinant IFN-α alone heightened the TNF-α response to LPS. Innate IFN-αβ and IFN-γ responses to LCMV exist in a delicate balance. To reduce priming for LPS-induced TNF-α during LCMV, deficiencies in both the IFN-αβ and IFN-γ receptors or STAT1, a transcription factor downstream to both IFNs, were required. These data demonstrate that early viral infection can enhance sensitivity to bacterial products, and that this sensitization can occur in part as a result of endogenously expressed IFN-αβ. This work also raises issues about potential complications associated with IFN-αβ therapies.
Respiratory Syncytial Virus Infection Results in Activation of Multiple Protein Kinase C Isoforms Leading to Activation of Mitogen-Activated Protein Kinase
Authors: Monick Martha M. , Staber Janice M. , Thomas Karl W. , Hunninghake Gary W. 
Published: April 2014

AbstractRespiratory syncytial virus (RSV) is an important respiratory pathogen that preferentially infects epithelial cells in the airway and causes a local inflammatory response. Very little is known about the second messenger pathways involved in this response. To characterize some of the acute response pathways involved in RSV infection, we used cultured human epithelial cells (A549) and optimal tissue culture-infective doses (TCID50) of RSV. We have previously shown that RSV-induced IL-8 release is linked to activation of the extracellular signal-related kinase (ERK) mitogen-activated protein kinase pathway. In this study, we evaluated the upstream events involved in ERK activation by RSV. RSV activated ERK at two time points, an early time point consistent with viral binding and a later sustained activation consistent with viral replication. We next evaluated the role of protein kinase C (PKC) isoforms in RSV-induced ERK kinase activity. We found that A549 cells contain the Ca2+-dependent isoforms α and β1, and the Ca2+-independent isoforms δ, ε, η, μ, θ, and ζ. Western analysis showed that RSV caused no change in the amounts of these isoforms. However, kinase activity assays demonstrated activation of isoform ζ within 10 min of infection, followed by a sustained activation of isoforms β1, δ, ε, and μ 24–48 h postinfection. A cell-permeable peptide inhibitor specific for the ζ isoform decreased early ERK kinase activation by RSV. Down-regulation of the other PKC isoforms with PMA blocked the late sustained activation of ERK by RSV. These studies suggest that RSV activates multiple PKC isoforms with subsequent downstream activation of ERK kinase.
IL-13 Overexpression Predisposes to Anaphylaxis Following Antigen Sensitization
Authors: Fallon Padraic G. , Emson Claire L. , Smith Philip , McKenzie Andrew N. J. 
Published: April 2014

Abstract
Anaphylaxis represents an extreme form of allergic reaction. This acute-phase component of allergy and asthma is triggered by allergen-induced degranulation of mast cells following the cross-linking of cell surface-bound, allergen-specific IgE, resulting in the liberation of inflammatory mediators and the development of bronchoconstriction. We used IL-13 transgenic mice to investigate the role of this Th2 cell-derived cytokine in the onset of allergic disease. Strikingly, IL-13-transgenic mice were highly predisposed to fatal anaphylaxis following Ag sensitization. This response correlated with substantially elevated levels of circulating Ag-specific IgE, mast cell degranulation, and histamine release. Furthermore, allergen exposure also induced phenotypic changes typical of asthma, including pulmonary fibrosis, goblet cell hyperplasia, elevated Th2 cytokines, eosinophilia, and airways occluded by mucus and Charcot-Leyden crystals. Expression of IL-4 was not required for the induction of IgE-mediated responses. These data represent the first characterization of a functional role for IL-13-induced IgE in the generation of immediate hypersensitivity reactions and highlight the importance of IL-13 in the development of the symptoms of atopy. The systemic regulation of this response makes these mice an important resource for studying atopic responses.
Surfactant Protein A Enhances Alveolar Macrophage Phagocytosis of Apoptotic Neutrophils
Authors: Schagat Trista L. , Wofford Jessica A. , Wright Jo Rae 
Published: April 2014

Abstract
Surfactant protein A (SP-A) is an innate immune molecule that binds foreign organisms that invade the lungs and targets them for phagocytic clearance by the resident pulmonary phagocyte, the alveolar macrophage (AM). We hypothesized that SP-A binds to and enhances macrophage uptake of other nonself particles, specifically apoptotic polymorphonuclear neutrophils (PMNs). PMNs are recruited into the lungs during inflammation, but as inflammation is resolved, PMNs undergo apoptosis and are phagocytosed by AMs. We determined that SP-A increases AM phagocytosis of apoptotic PMNs 280 ± 62% above the no protein control value. The increase is dose dependent, and heat-treated SP-A still enhanced uptake, whereas deglycosylated SP-A had significantly diminished ability to enhance phagocytosis. Surfactant protein D also increased phagocytosis of apoptotic PMNs by ∼125%. However, other proteins that are structurally homologous to SP-A, mannose-binding lectin and complement protein 1q, did not. SP-A enhances phagocytosis via an opsonization-dependent mechanism and binds apoptotic PMNs ∼4-fold more than viable PMNs. Also, binding of SP-A to apoptotic PMNs does not appear to involve SP-A’s lectin domain. These data suggest that the pulmonary collectins SP-A and SP-D facilitate the resolution of inflammation by accelerating apoptotic PMN clearance.
Functional Expression of IL-9 Receptor by Human Neutrophils from Asthmatic Donors: Role in IL-8 Release
Authors: Abdelilah Soussi Gounni , Latifa Koussih , Esra Nutku , Cameron Lisa , Bouchaib Lamkhioued , Nicolaides Nicholas C. , Levitt Roy C. , Hamid Qutayba 
Published: April 2014

Abstract
Human polymorphonuclear neutrophils (PMNs) express surface receptors for various inflammatory mediators, including IgE and IL-4. Recently, the IL-9R locus has been genetically linked to asthma and bronchial hyperresponsiveness in humans. In this study, we evaluated expression of the IL-9R and the effect of IL-9 on human PMNs. RT-PCR analysis showed the presence of IL-9Rα-chain mRNA in PMN RNA preparations from asthmatic patients. Using FACS analysis, surface expression of IL-9Rα was detected on PMNs freshly isolated from asthmatics, and to a lesser extent on normal controls. In addition, protein expression of IL-9Rα was also detected in peripheral blood and bronchoalveolar lavage PMNs. Furthermore, functional studies showed that IL-9 stimulation of PMNs results in the release of IL-8 in a concentration-dependent manner. The anti-IL-9 neutralizing Ab suppressed this effect, but had no effect on GM-CSF-induced IL-8 release from PMNs. Taken together, these findings suggest a novel role for PMNs in allergic disease through the expression and activation of the IL-9R.
IL-4 Exacerbates Disease in a Th1 Cell Transfer Model of Colitis
Authors: Fort Madeline M. , Lesley Robin , Davidson Natalie J. , Menon Satish , Brombacher Frank , Leach Michael W. , Rennick Donna M. 
Published: April 2014

Abstract
IL-4 is associated with Th2-type immune responses and can either inhibit or, in some cases, promote Th1-type responses. We tested the effect of IL-4 treatment on the development of inflammation in the CD4+CD45RBhigh T cell transfer model of colitis, which has been characterized as a Th1-dependent disease. IL-4 treatment significantly accelerated the development of colitis in immunodeficient recipients (recombinase-activating gene-2 (Rag2)−/−) of CD4+CD45RBhigh T cells. Quantitative analysis of mRNA expression in the colons of IL-4-treated mice showed an up-regulation of both Th1- and Th2-associated molecules, including IFN-γ, IP-10, MIG, CXCR3, chemokine receptor-8, and IL-4. However, cotreatment with either IL-10 or anti-IL-12 mAb effectively blocked the development of colitis in the presence of exogenous IL-4. These data indicate that IL-4 treatment exacerbates a Th1-mediated disease rather than induces Th2-mediated inflammation. As other cell types besides T cells express the receptor for IL-4, the proinflammatory effects of IL-4 on host cells in Rag2−/− recipients were assessed. IL-4 treatment was able to moderately exacerbate colitis in Rag2−/− mice that were reconstituted with IL-4Rα-deficient (IL-4Rα−/−) CD4+CD45RBhigh T cells, suggesting that the IL-4 has proinflammatory effects on both non-T and T cells in this model. IL-4 did not cause colitis in Rag2−/− mice in the absence of T cells, but did induce an increase in MHC class II expression in the lamina propria of the colon, which was blocked by cotreatment with IL-10. Together these results indicate that IL-4 can indirectly promote Th1-type inflammation in the CD4+CD45RBhigh T cell transfer model of colitis.
Blockade of TGF-β Signaling in T Cells Prevents the Development of Experimental Glomerulonephritis
Authors: Kanamaru Yutaka , Nakao Atsuhito , Mamura Mizuko , Suzuki Yusuke , Shirato Isao , Okumura Ko , Tomino Yasuhiko , Ra Chisei 
Published: April 2014

Abstract
Anti-glomerular basement membrane (GBM) Ab-induced glomerulonephritis (GN) at late stage is thought to be mediated by T cells. However, signaling pathways of T cells that are involved in the development of anti-GBM Ab-induced GN are unclear. We have recently established transgenic mice expressing Smad7, an inhibitor of TGF-β signaling, in mature T cells, where signaling by TGF-β was blocked specifically in T cells. In this study, we showed that anti-GBM Ab-induced GN was suppressed in several measures in the transgenic mice including the severity of glomerular changes, proteinuria, renal function, and CD4 T cell infiltration into the glomeruli without down-regulation of CD62 ligand (CD62L) (L-selectin) expression on CD4 T cells. Furthermore, treatment with the soluble fusion protein of CD62L and IgG enhanced anti-GBM Ab-induced GN. These findings indicated that blockade of TGF-β signaling in T cells prevented the development of anti-GBM Ab-induced GN. Because CD62L on T cells appears to be inhibitory for the development of anti-GBM Ab-induced GN, persistent expression of CD62L on CD4 T cells may explain, at least in part, the suppression of anti-GBM Ab-induced GN in the transgenic mice. Our findings suggest that the development of anti-GBM Ab-induced GN requires TGF-β/Smad signaling in T cells.
Differential Susceptibility of Heart, Skin, and Islet Allografts to T Cell-Mediated Rejection
Authors: Jones Nick D. , Turvey Stuart E. , Van Maurik Andre , Hara Masaki , Kingsley Cherry I. , Smith Clare H. , Mellor Andrew L. , Morris Peter J. , Wood Kathryn J. 
Published: April 2014

AbstractAlthough it is widely accepted that there is a hierarchy in the susceptibility of different allografts to rejection, the mechanisms responsible are unknown. We show that the increased susceptibility of H-2Kb+ skin and islet allografts to rejection is not based on their ability to activate more H-2Kb-specific T cells in vivo; heart allografts stimulate the activation and proliferation of many more H-2Kb-specific T cells than either skin or islet allografts. Rejection of all three types of graft generate memory cells by 25 days posttransplant. These data provide evidence that neither tissue-specific Ags nor, surprisingly, the number of APCs carried in the graft dictate their susceptibility to T cell-mediated rejection and suggest that the graft microenvironment and size may play a more important role in determining the susceptibility of an allograft to rejection and resistance to tolerance induction.
Vβ6+ and Vβ4+ T Cells Exert Cooperative Activity in Clearance of Secondary Infection with Histoplasma capsulatum
Authors: Gomez Francisco J. , Woodward Erin O. , Pilcher-Roberts Robyn , Gibbons Reta S. , Deepe George S. 
Published: April 2014

Abstract
We previously studied the lung Vβ TCR repertoire of C57BL/6 mice during primary infection with the pathogen Histoplasma capsulatum. We observed a consistent oligoclonal expansion of Vβ4+ T cells during the peak of infection and early stages of resolution. The Vβ4+ family played a role in protective immunity against the fungus. Depletion of this subpopulation of T cells hindered optimal clearance of infection from tissues. In this report we analyze the flux of the Vβ TCR repertoire in the lungs of C57BL/6 mice with reinfection histoplasmosis. We observed a significant increase in Vβ6+ T cells on days 7, 10, and 14, the peak and early resolution phases of infection. This skewing was preceded by an increased number of memory T cells within Vβ6+ cells. The VDJ sequences of Vβ6 chains were oligoclonal during the early stages of the infection, suggesting that the expansion was driven by a small number of Ags. More than 96% of the expanded Vβ6+ cells were CD4+. Depletion of Vβ6+ T cells but not Vβ4+ T cells induced a modest but significant delay in fungal clearance. Simultaneous depletion of Vβ4+ and Vβ6+ T cells induced a more pronounced impairment of host resistance. These studies illustrate the dynamic interactions between Vβ families in the response to microbial challenge.
Cutting Edge: Is Vasoactive Intestinal Peptide a Type 2 Cytokine?
Authors: Delgado Mario , Ganea Doina 
Published: April 2014

AbstractA component of the chemical language shared by the immune and nervous system is the expression of neuropeptides by immune cells. Vasoactive intestinal peptide (VIP) was shown to be produced by T lymphocytes. Here we investigate whether T cell subsets differentially express VIP. Our studies indicate that, upon specific Ag stimulation, Th2 and T2 cells, but not Th1 and T1 cells derived from TCR transgenic (Tg) mice, express VIP mRNA and protein, and secrete VIP. Following immunization with the specific Ag, significant levels of VIP are present in the serum of syngeneic, non-Tg hosts that receive Th2, but not Th1 Tg cells. Th2 Tg cells recovered from the non-Tg hosts immunized with the specific Ag, but not with an irrelevant Ag, express intracellular VIP. Because VIP is produced by Ag-stimulated type 2 T cells, and differentially affects Th1 and Th2 cells, could VIP be viewed as a type 2 cytokine?