bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histone Deacetylases Inhibit IFN-γ-Inducible Gene Expression in Mouse Trophoblast Cells
Authors: Choi Jason C. , Holtz Renae , Murphy Shawn P. 
Published: May 2009

Abstract
Trophoblast cells are the first cells to differentiate from the developing mammalian embryo, and they subsequently form the blastocyst-derived component of the placenta. IFN-γ plays critical roles in activating innate and adaptive immunity, as well as apoptosis. In mice, IFN-γ is produced in the pregnant uterus, and is essential for formation of the decidual layer of the placenta and remodeling of the uterine vasculature. Responses of mouse trophoblast cells to IFN-γ appear to be selective, for IFN-γ activates MHC class I expression and enhances phagocytosis, but fails to activate either MHC class II expression or apoptosis in these cells. To investigate the molecular basis for the selective IFN-γ responsiveness of mouse trophoblast cells, IFN-γ-inducible gene expression was examined in the trophoblast cell lines SM9 and M-11, trophoblast stem cells, and trophoblast stem cell-derived giant cells. IFN-γ-inducible expression of multiple genes, including IFN regulatory factor-1 (IRF-1), was significantly reduced in trophoblast cells compared with fibroblast cells. Decreased IRF-1 mRNA expression in trophoblast cells was due to a reduced rate of IRF-1 transcription relative to fibroblast cells. However, no impairment of STAT-1 tyrosine phosphorylation or DNA-binding capacity was observed in IFN-γ-treated mouse trophoblast cells. Importantly, histone deacetylase (HDAC) inhibitors significantly enhanced IFN-γ-inducible gene expression in trophoblast cells, but not fibroblasts. Our collective studies demonstrate that IFN-γ-inducible gene expression is repressed in mouse trophoblast cells by HDACs. We propose that HDAC-mediated inhibition of IFN-γ-inducible gene expression in mouse trophoblast cells may contribute to successful pregnancy by preventing activation of IFN-γ responses that might otherwise facilitate the destruction of the placenta.
IL-31-IL-31R Interactions Limit the Magnitude of Th2 Cytokine-Dependent Immunity and Inflammation following Intestinal Helminth Infection
Authors: Perrigoue Jacqueline G. , Zaph Colby , Guild Katherine , Du Yurong , Artis David 
Published: May 2009

Abstract
IL-31 is a recently identified cytokine made predominantly by CD4+ Th2 cells and its receptor, IL-31R, is expressed by a number of cell types including monocytes, epithelial cells, and T cells. Originally identified as a potential mediator of inflammation in the skin, we recently reported a novel function for endogenous IL-31R interactions in limiting type 2 inflammation in the lung. However, whether IL-31-IL-31R interactions regulate immunity or inflammation at other mucosal sites, such as the gut, is unknown. In this study, we report a regulatory role for IL-31-IL-31R interactions in the intestine following infection with the gastrointestinal helminth Trichuris muris, immunity to which is critically dependent on CD4+ Th2 cells that produce IL-4 and IL-13. IL-31Rα was constitutively expressed in the colon and exposure to Trichuris induced the expression of IL-31 in CD4+ T cells. In response to Trichuris infection, IL-31Rα−/− mice exhibited increased Th2 cytokine responses in the mesenteric lymph nodes and elevated serum IgE and IgG1 levels compared with wild type mice. IL-31Rα−/− mice also displayed enhanced goblet cell hyperplasia and a marked increase in secretion of goblet cell-derived resistin-like molecule β into the intestinal lumen. Consistent with their exacerbated type 2 inflammatory responses, IL-31Rα−/− mice exhibited accelerated expulsion of Trichuris with significantly decreased worm burdens compared with their wild type counterparts early following infection. Collectively, these data provide the first evidence of a function for IL-31-IL-31R interactions in limiting the magnitude of type 2 inflammatory responses within the intestine.
Impaired Priming and Activation of the Neutrophil NADPH Oxidase in Patients with IRAK4 or NEMO Deficiency
Authors: Singh Anjali , Zarember Kol A. , Kuhns Douglas B. , Gallin John I. 
Published: May 2009

Abstract
The NADPH oxidase (NOX), an oligomeric enzyme, plays a key role in polymorphonuclear neutrophil (PMN)-mediated host defense by producing cytotoxic superoxide anion (O2). Whereas in vitro and biochemical studies have examined the assembly and activation of this important host immune defense system, few studies have examined the function of NOX in human patients with primary immunodeficiency other than chronic granulomatous disease. We studied the activation of NOX in PMN from patients with two distinct immunodeficiencies, IL-1R-associated kinase (IRAK)4 deficiency and NF-κB essential modulator (NEMO or IκB kinase γ) deficiency. We observed impaired O2 generation by LPS-treated and fMLP-activated IRAK4-deficient PMN that correlated with decreased phosphorylation of p47phox and subnormal translocation of p47phox, p67phox, Rac2, and gp91phox/Nox2 to the membranes indicating that TLR4 signaling to the NOX activation pathway requires IRAK4. NEMO-deficient PMN generated significantly less O2 in response to LPS-primed fMLP and translocated less p67phox than normal PMN, although p47phox and Rac2 translocation were normal. Generally, responses of NEMO-deficient cells were intermediate between IRAK4-deficient cells and normal cells. Decreased LPS- and fMLP-induced phosphorylation of p38 MAPK in both IRAK4- and NEMO-deficient PMN implicates additional signal transduction pathways in regulating PMN activation by LPS and fMLP. Decreased activation of NOX may contribute to the increased risk of infection seen in patients with IRAK4 and NEMO deficiency.
Lack of Functional P-Selectin Ligand Exacerbates Salmonella Serovar Typhimurium Infection
Authors: Kum Winnie W. S. , Lee Sansan , Grassl Guntram A. , Bidshahri Roza , Hsu Kimberly , Ziltener Hermann J. , Finlay B. Brett 
Published: May 2009

Abstract
The selectin family of adhesion molecules mediates the recruitment of immune cells to the site of inflammation, which is critical for host survival of infection. To characterize the role of selectins in host defense against Salmonella Typhimurium infection, wild-type (WT) mice and mice lacking P-selectin glycoprotein ligand-1 (PSGL-1), P-, E-, or L-selectin, or the glycosyltransferase C2GlcNAcT-I (core 2) were infected using a Salmonella acute gastroenteritis model. Mice were monitored for survival and assessed for intestinal inflammation at 1 and 4 days postinfection. Infected mice lacking core 2, PSGL-1, or P-selectin showed a more pronounced morbidity and a significantly higher mortality rate associated with higher bacterial load and proinflammatory cytokine production, including that of TNF-α, MCP-1, and IL-6, from the colons at 4 days postinfection as compared with WT control. Surprisingly, at 1 day postinfection, more severe inflammation and higher neutrophil infiltration were observed in the ceca of mice lacking core 2, PSGL-1, or P-selectin compared with WT control. Enhanced levels of α4β7+ and MAdCAM-1+ cells were observed in the ceca of infected mice lacking core 2, PSGL-1, or P-selectin. Neutrophil recruitment, cecal inflammation, and mortality rates were dramatically reduced in infected P-selectin knockout mice receiving blocking mAb to α4β7 integrin, indicating that this alternative adhesion molecule may attempt to compensate for the loss of selectins in neutrophil recruitment. These results demonstrate a definitive phenotypic abnormality in mice lacking core 2, PSGL-1, or P-selectin, suggesting that the interaction of functional PSGL-1 with P-selectin is an important process in host defense against Salmonella infection.
Tumor Regulatory T Cells Potently Abrogate Antitumor Immunity
Authors: Liu Zuqiang , Kim Jin H. , Falo Louis D. , You Zhaoyang 
Published: May 2009

Abstract
Regulatory T cell (Treg) from mice bearing a breast tumor were elevated (tumor Treg). In vitro, whereas tumor Treg ability to inhibit tumor-primed CD4+ T cell activity is comparable to Treg from naive mice (naive Treg), only tumor Treg suppress naive CD8+ T cell activation and DC function. Neither tumor Treg nor naive Treg can suppress antitumor immunity at the effector phase of the immune response induced by adoptively transferred tumor-primed CD4+ T cells. This is consistent with the observation that, in this model, neither tumor Treg nor naive Treg can inhibit effectors in vitro or in vivo. However, tumor Treg abrogate tumor-specific CD8+ T cell responses in tumor-draining lymph nodes and antitumor immunity at the early stage of the immune response induced by adoptively transferred tumor-primed CD4+ T cells. These data indicate that, in this model, tumor Treg potently abrogate tumor-specific CD8+ T cell responses in tumor-draining lymph nodes, thereby suppressing antitumor immunity at the early stage of the immune response induced by adoptively transferred tumor-primed CD4+ T cells.
Neisseria gonorrhoeae Activates the Proteinase Cathepsin B to Mediate the Signaling Activities of the NLRP3 and ASC-Containing Inflammasome
Authors: Duncan Joseph A. , Gao Xi , Huang Max Tze-Han , O'Connor Brian P. , Thomas Christopher E. , Willingham Stephen B. , Bergstralh Daniel T. , Jarvis Gary A. , Sparling P. Frederick , Ting Jenny P.-Y. 
Published: May 2009

Abstract
Neisseria gonorrhoeae is a common sexually transmitted pathogen that significantly impacts female fertility, neonatal health, and transmission of HIV worldwide. N. gonorrhoeae usually causes localized inflammation of the urethra and cervix by inducing production of IL-1β and other inflammatory cytokines. Several NLR (nucleotide-binding domain, leucine-rich repeat) proteins are implicated in the formation of pro-IL-1β-processing complexes called inflammasomes in response to pathogens. We demonstrate that NLRP3 (cryopyrin, NALP3) is the primary NLR required for IL-1β/IL-18 secretion in response to N. gonorrhoeae in monocytes. We also show that N. gonorrhoeae infection promotes NLRP3-dependent monocytic cell death via pyronecrosis, a recently described pathway with morphological features of necrosis, including release of the strong inflammatory mediator HMBG1. Additionally, N. gonorrhoeae activates the cysteine protease cathepsin B as measured by the breakdown of a cathepsin B substrate. Inhibition of cathepsin B shows that this protease is an apical controlling step in the downstream activities of NLRP3 including IL-1β production, pyronecrosis, and HMGB1 release. Nonpathogenic Neisseria strains (Neisseria cinerea and Neisseria flavescens) do not activate NLRP3 as robustly as N. gonorrhoeae. Conditioned medium from N. gonorrhoeae contains factors capable of initiating the NLRP3-mediated signaling events. Isolated N. gonorrhoeae lipooligosaccharide, a known virulence factor from this bacterium that is elaborated from the bacterium in the form of outer membrane blebs, activates both NLRP3-induced IL-1β secretion and pyronecrosis. Our findings indicate that activation of NLRP3-mediated inflammatory response pathways is an important venue associated with host response and pathogenesis of N. gonorrhoeae.
Tetraspanin CD9 Negatively Regulates Lipopolysaccharide-Induced Macrophage Activation and Lung Inflammation
Authors: Suzuki Mayumi , Tachibana Isao , Takeda Yoshito , He Ping , Minami Seigo , Iwasaki Takeo , Kida Hiroshi , Goya Sho , Kijima Takashi , Yoshida Mitsuhiro , Kumagai Toru , Osaki Tadashi , Kawase Ichiro 
Published: May 2009

Abstract
Tetraspanins facilitate the formation of multiple molecular complexes at specialized membrane microdomains and regulate cell activation and motility. In the present study, the role of tetraspanin CD9 in LPS-induced macrophage activation and lung inflammation was investigated in vitro and in vivo. When CD9 function was ablated with mAb treatment, small interfering RNA transfection, or gene knockout in RAW264.7 cells or bone marrow-derived macrophages, these macrophages produced larger amounts of TNF-α, matrix metalloproteinase-2, and -9 upon stimulation with LPS in vitro, when compared with control cells. Sucrose gradient analysis revealed that CD9 partly colocalized with the LPS-induced signaling mediator, CD14, at low-density light membrane fractions. In CD9 knockout macrophages, CD14 expression, CD14 and TLR4 localization into the lipid raft, and their complex formation were increased whereas IκBα expression was decreased when compared with wild-type cells, suggesting that CD9 prevents the formation of LPS receptor complex. Finally, deletion of CD9 in mice enhanced macrophage infiltration and TNF-α production in the lung after intranasal administration of LPS in vivo, when compared with wild-type mice. These results suggest that macrophage CD9 negatively regulates LPS response at lipid-enriched membrane microdomains.
CD8 T Cells Producing IL-17 and IFN-γ Initiate the Innate Immune Response Required for Responses to Antigen Skin Challenge
Authors: Kish Danielle D. , Li Xiaoxia , Fairchild Robert L. 
Published: May 2009

Abstract
Effector CD8 T cell recruitment into the skin in response to Ag challenge requires prior CXCL1/KC-directed neutrophil infiltration. Mechanisms inducing CXCL1 production and the dynamics of neutrophil-CD8 T cell interactions during elicitation of Ag-specific responses in the skin were investigated. CXCL1 and CXCL2/MIP-2 were produced within 3–6 h of Ag challenge at 10-fold higher levels in skin challenge sites of Ag-sensitized vs nonsensitized mice. In the challenge sites of sensitized mice this production decreased at 6–9 h postchallenge to near the levels observed in skin challenge sites of nonsensitized mice but rose to a second peak 12 h after challenge. The elevated early neutrophil chemoattractant production at 3–6 h after skin challenge of sensitized animals required both IFN-γ and IL-17, produced by distinct populations of Ag-primed CD8 T cells in response to Ag challenge. Although induced by the Ag-primed CD8 T cells, the early CXCL1 and CXCL2 production was accompanied by neutrophil but not CD8 T cell infiltration into the skin Ag challenge site. Infiltration of the CD8 T cells into the challenge site was not observed until 18–24 h after challenge. These results demonstrate an intricate series of early interactions between Ag-specific and innate immune components that regulate the sequential infiltration of neutrophils and then effector T cells into the skin to mediate an immune response.
Impaired Mast Cell-Driven Immune Responses in Mice Lacking the Transcription Factor NFATc2
Authors: Becker Marc , Heib Valeska , Klein Matthias , Doener Fatma , Bopp Tobias , Taube Christian , Radsak Markus , Schild Hansjörg , Schmitt Edgar , Stassen Michael 
Published: May 2009

Abstract
The three calcium-dependent factors NFATc1, c2, and c3 are expressed in cells of the immune system and play pivotal roles in modulating cellular activation. With regard to NFATc2, it was reported that NFATc2-deficient mice display increased immune responses in several models for infection and allergy in vivo. This led to the assumption that NFATc2 is involved in the maintenance of immune homeostasis. Using the synthetic TLR7 agonist imiquimod as an adjuvant in epicutaneous peptide immunization, we observed that both the inflammatory reaction and the peptide-specific CTL response are severely impaired in NFATc2-deficient mice. Detailed analyses revealed that early production of proinflammatory cytokines, lymph node hypertrophy, and migration of Langerhans cells are strongly reduced in NFATc2-deficient animals. With the aid of mast cell-deficient mice and reconstitution experiments using mast cells derived from either NFATc2-deficient mice or wild-type controls, we were able to show that NFATc2 expressed in mast cells is critical for the initiation of inflammation, migration of Langerhans cells, and the development of full-blown CTL responses following epicutaneous immunization. Thus, NFATc2 is an important factor controlling mast cell accessory function at the interface of innate and adaptive immunity.
Differentiation of Central Memory CD8 T Cells Is Independent of CD62L-Mediated Trafficking to Lymph Nodes
Authors: Wirth Thomas C. , Badovinac Vladimir P. , Zhao Lichao , Dailey Morris O. , Harty John T. 
Published: May 2009

Abstract
CD62L (L-selectin) is a key regulator of T cell trafficking, and its surface expression on activated T cells is modulated to control T cell access to lymph nodes after acute infections. In memory T cells, CD62L is the most frequently used marker to define central memory T cells, a population that provides enhanced protection against most, but not all, pathogens. Early access of CD62Lpos effector T cells to lymph nodes has been proposed to result in preferential central memory T cell differentiation, but direct proof for the involvement of lymph node homing in memory T cell differentiation is lacking. In this study, we show that central memory lineage commitment in CD8 T cells is unaltered by enhanced entry into lymph nodes as a result of constitutive CD62L expression, and that equal numbers of effector and central memory CD8 T cells develop in the absence of CD62L-mediated lymph node trafficking. Our results suggest that CD62L is not a deterministic marker of central memory T cell differentiation, thus providing new insight into the process of memory CD8 T cell generation.
M1 and M2a Polarization of Human Monocyte-Derived Macrophages Inhibits HIV-1 Replication by Distinct Mechanisms
Authors: Cassol Edana , Cassetta Luca , Rizzi Chiara , Alfano Massimo , Poli Guido 
Published: May 2009

AbstractThe capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines and other extracellular stimuli. In this study, we demonstrate that cytokine-induced polarization of human monocyte-derived macrophage (MDM) into either classical (M1) or alternatively activated (M2a) MDM is associated with a reduced capacity to support productive CCR5-dependent (R5) HIV-1 infection. M1 polarization was associated with a significant down-regulation of CD4 receptors, increased secretion of CCR5-binding chemokines (CCL3, CCL4, and CCL5), and a &gt;90% decrease in HIV-1 DNA levels 48-h postinfection, suggesting that the inhibition occurred at an early preintegration step in the viral life cycle. In contrast, M2a polarization had no effect on either HIV-1 DNA or protein expression levels, indicating that inhibition occurred at a late/postintegration level in the viral life cycle. M2a inhibition was sustained for up to 72-h postinfection, whereas M1-effects were more short-lived. Most phenotypic and functional changes were fully reversible 7 days after removal of the polarizing stimulus, and a reciprocal down-regulation of M1-related chemokines and cytokines was observed in M2a MDM and vice versa. Since reversion to a nonpolarized MDM state was associated with a renewed capacity to support HIV replication to control levels, M1/M2a polarization may represent a mechanism that allows macrophages to cycle between latent and productive HIV-1 infection.
In Vivo Enhancement of Peptide Display by MHC Class II Molecules with Small Molecule Catalysts of Peptide Exchange
Authors: Call Melissa J. , Xing Xuechao , Cuny Gregory D. , Seth Nilufer P. , Altmann Daniel M. , Fugger Lars , Krogsgaard Michelle , Stein Ross L. , Wucherpfennig Kai W. 
Published: May 2009

Abstract
Rapid binding of peptides to MHC class II molecules is normally limited to a deep endosomal compartment where the coordinate action of low pH and HLA-DM displaces the invariant chain remnant CLIP or other peptides from the binding site. Exogenously added peptides are subject to proteolytic degradation for extended periods of time before they reach the relevant endosomal compartment, which limits the efficacy of peptide-based vaccines and therapeutics. In this study, we describe a family of small molecules that substantially accelerate the rate of peptide binding to HLA-DR molecules in the absence of HLA-DM. A structure-activity relationship study resulted in analogs with significantly higher potency and also defined key structural features required for activity. These compounds are active over a broad pH range and thus enable efficient peptide loading at the cell surface. The small molecules not only enhance peptide presentation by APC in vitro, but are also active in vivo where they substantially increase the fraction of APC on which displayed peptide is detectable. We propose that the small molecule quickly reaches draining lymph nodes along with the coadministered peptide and induces rapid loading of peptide before it is destroyed by proteases. Such compounds may be useful for enhancing the efficacy of peptide-based vaccines and other therapeutics that require binding to MHC class II molecules.
Autoreactive Anti-DNA Transgenic B Cells in Lupus-Prone New Zealand Black/New Zealand White Mice Show Near Perfect L Chain Allelic Exclusion
Authors: Makdasi Efi , Fischel Ruth , Kat Inbal , Eilat Dan 
Published: May 2009

Abstract
Recent work on B cell tolerance and autoimmunity has suggested the L chain allelic inclusion is a property of autoreactive B cells and is closely linked to receptor editing. Allelic inclusion could rescue autoreactive B cells from clonal deletion by reducing their effective BCR surface density. We have investigated this phenomenon in anti-DNA producing hybridomas, derived from different strains of Ig gene-targeted, lupus-prone NZB/NZW mice. Our results indicate that isotype and allelic exclusion was strictly maintained in most high- and low-affinity, edited and nonedited, anti-DNA transgenic B cells. However, a substantial fraction of the anti-DNA hybridomas expressed a very restricted set of nonproductively rearranged L chain mRNA, in addition to the productive anti-DNA L chain. The aberrant L chains could have a role in the selection and survival of autoreactive B cells in these autoimmune mice.
Regulatory T Cell Suppression Is Potentiated by Target T Cells in a Cell Contact, IL-35- and IL-10-Dependent Manner
Authors: Collison Lauren W. , Pillai Meenu R. , Chaturvedi Vandana , Vignali Dario A. A. 
Published: May 2009

Abstract
Regulatory T cells (Treg) are believed to suppress conventional T cell (Tconv) proliferation in vitro in a contact-dependent, cytokine-independent manner, based in part on experiments in which Treg and Tconv are separated by a permeable membrane. We show that the production of IL-35, a novel inhibitory cytokine expressed by natural Treg, increases substantially following contact with Tconv. Surprisingly, Treg were able to mediate potent suppression of Tconv across a permeable membrane when placed in direct contact with Tconv in the upper chamber of a Transwell plate. Suppression was IL-35 and IL-10 dependent, and Tconv activation was required for maximal potentiation of Treg suppression. These data suggest that it is the induction of suppression, rather than the function of Treg that is obligatorily contact dependent.