bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-4 Exacerbates Anaphylaxis
Authors: Strait Richard T. , Morris Suzanne C. , Smiley Kristi , Urban Joseph F. , Finkelman Fred D. 
Published: April 2014

Abstract
We evaluated whether IL-4, a cytokine critical for inducing allergic responses, also contributes to the effector phase of allergy. Pretreatment of mice with IL-4 or the related cytokine, IL-13, rapidly and dramatically increased the severity of anaphylaxis induced by cross-linking FcεRI or FcγRIII. This effect was inhibited by endogenously produced IFN-γ, was T cell-, B cell-, and common γ-chain-independent, and required IL-4Rα and Stat6. IL-4Rα signaling also enhanced anaphylaxis in mice infected with a nematode parasite that stimulates IL-4/IL-13 production. IL-4 exacerbated anaphylaxis by acting synergistically with vasoactive mediators to increase vascular permeability. Synergy between IL-4 and vasoactive mediators during the effector phase of allergic inflammation may both contribute to allergic immunopathology and enhance protective immunity against gastrointestinal worms.
Unique Regulation of CCL18 Production by Maturing Dendritic Cells
Authors: Vulcano Marisa , Struyf Sofie , Scapini Patrizia , Cassatella Marco , Bernasconi Sergio , Bonecchi Raffaella , Calleri Angelica , Penna Giuseppe , Adorini Luciano , Luini Walter , Mantovani Alberto , Van Damme Jo , Sozzani Silvano 
Published: April 2014

Abstract
Dendritic cells (DC) orchestrate the trafficking of lymphocytes by secreting chemokines with different specificity and function. Chemokines are produced at higher levels by mature DC. This study shows that CCL18 is one of the most abundant chemokines produced by immature DC. In contrast to all other chemokines investigated to date, CCL18 was selectively down-regulated during the maturation process induced by LPS, TNF, CD40 ligand, Staphylococcus aureus Cowan I, Candida albicans, and influenza virus. IL-10 and vitamin D3, two known inhibitors of DC differentiation and function, strongly promoted CCL18 secretion, whereas IFN-γ, a costimulator of DC function, inhibited its production. IL-10 also induced CCL18 secretion in blood myeloid DC. No CCL18 secretion was observed in blood plasmacytoid DC. The opposite pattern of regulation was observed for CCL20, a prototypic inflammatory chemokine. CCL18 was found to be a chemotactic factor for immature DC. Therefore, CCL18 may act as a chemotactic signal that promotes the colocalization of immature DC with naive T lymphocytes in an IL-10-dominated environment with the consequent generation of T regulatory cells. These characteristics suggest that CCL18 may be part of an inhibitory pathway devoted to limiting the generation of specific immune responses at peripheral sites.
The Extracellular Matrix and Cytokines Regulate Microglial Integrin Expression and Activation
Authors: Milner Richard , Campbell Iain L. 
Published: April 2014

Abstract
Microglia are the primary immune effector cells resident within the CNS, whose activation into migratory, phagocytic cells is associated with increased expression of cell adhesion molecules of the integrin family. To determine which specific factors are important regulators of microglial activation and integrin expression, we have examined the influence of individual cytokines and extracellular matrix (ECM) substrates by quantifying cell surface expression of MHC and individual integrins by flow cytometry. We found that the proinflammatory cytokines TNF and IFN-α promoted microglial activation, as assessed by amoeboid morphology and increased expression of MHC class I, and also increased expression of the α4β1 and Mac-1 integrins. In contrast, TGF-β1 had the opposite effect and was dominant over the other cytokines. Furthermore, the ECM substrates fibronectin and vitronectin, but not laminin, also promoted microglial activation and increased expression of the α4β1, α5β1 and Mac-1 integrins, but significantly, the influence of fibronectin and vitronectin was not diminished by TGF-β1. Taken together, this work suggests that, in addition to cytokines, the ECM represents an important regulatory influence on microglial activity. Specifically, it implies that increases in the local availability of fibronectin or vitronectin, as a result of blood-brain barrier breakdown or increased expression in different pathological states of the CNS, could induce microglial activation and increased expression of integrins.
STAT4 Signal Pathways Regulate Inflammation and Airway Physiology Changes in Allergic Airway Inflammation Locally Via Alteration of Chemokines
Authors: Raman Kavita , Kaplan Mark H. , Hogaboam Cory M. , Berlin Aaron , Lukacs Nicholas W. 
Published: April 2014

AbstractMice homozygous for the STAT4-null mutation were sensitized to cockroach Ag, challenged intratracheally 21 days later, and compared with STAT4-competent allergic mice. The STAT4−/− mice showed significant decreases in airway hyperreactivity (AHR) and peribronchial eosinophils compared with wild-type controls. In addition, pulmonary levels of chemokines were decreased in the STAT4−/− mice, including CC chemokine ligand (CCL)5, CCL6, CCL11, and CCL17. However, levels of Th2-type cytokines, such as IL-4 and IL-13, as well as serum IgE levels were similar in the two groups. Transfer of splenic lymphocytes from sensitized wild-type mice into sensitized STAT4−/− mice did not restore AHR in the mutant mice. Furthermore, chemokine production and peribronchial eosinophilia were not restored during the cellular transfer experiments. Thus, it appears that STAT4 expression contributes to a type 2 process such as allergen-induced chemokine production and AHR. In additional studies, competent allergic mice were treated with anti-IL-12 locally in the airways at the time of allergen rechallenge. These latter studies also demonstrated a decrease in AHR. Altogether, these data suggest that STAT4-mediated pathways play a role locally within the airway for the exacerbation of the allergen-induced responses.
Modulation of Cutaneous Inflammation by Angiotensin-Converting Enzyme
Authors: Scholzen Thomas E. , Ständer Sonja , Riemann Helge , Brzoska Thomas , Luger Thomas A. 
Published: April 2014

AbstractCutaneous neurogenic inflammation is a complex biological response of the host immune system to noxious stimuli. Present evidence suggests that zinc metalloproteases may play an important role in the regulation of neurogenic inflammation by controlling the local availability of neuropeptides, such as substance P (SP), that are capable of initiating or amplifying cutaneous inflammation after release from sensory nerves. To address the hypothesis that the dipeptidyl carboxypeptidase angiotensin-converting enzyme (ACE) is capable of modulating skin inflammation, we have analyzed murine allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD) using wild-type C57BL/6J (ACE+/+) or genetically engineered mice with a heterozygous deletion of somatic ACE (ACE+/−). In 2,4-dinitro-1-fluorobenzene-sensitized ACE+/− mice, ACD was significantly augmented in comparison to ACE+/+ controls as determined by the degree of ear swelling after exposure to hapten. Likewise, systemic treatment of ACE+/+ mice with the ACE inhibitor captopril before sensitization or elicitation of ACD significantly augmented the ACD response. In contrast, local damage and neuropeptide depletion of sensory nerves following capsaicin, injection of a bradykinin B2, or a SP receptor antagonist before sensitization significantly inhibited the augmented effector phase of ACD in mice with functionally absent ACE. However, in contrast to ACD, the response to the irritant croton oil was not significantly altered in ACE+/− compared with ACE+/+ mice. Thus, ACE by degrading bradykinin and SP significantly controls cutaneous inflammatory responses to allergens but not to irritants, which may explain the frequently observed exacerbation of inflammatory skin disease in patients under medication with ACE inhibitors.
Sodium Phenylacetate Inhibits Adoptive Transfer of Experimental Allergic Encephalomyelitis in SJL/J Mice at Multiple Steps
Authors: Dasgupta Subhajit , Zhou You , Jana Malabendu , Banik Naren L. , Pahan Kalipada 
Published: April 2014

Abstract
Experimental allergic encephalomyelitis (EAE) is the animal model for multiple sclerosis. The present study underlines the importance of sodium phenylacetate (NaPA), a drug approved for urea cycle disorders, in inhibiting the disease process of adoptively transferred EAE in female SJL/J mice at multiple steps. Myelin basic protein (MBP)-primed T cells alone induced the expression of NO synthase (iNOS) and the activation of NF-κB in mouse microglial cells through cell-cell contact. However, pretreatment of MBP-primed T cells with NaPA markedly inhibited its ability to induce microglial expression of iNOS and activation of NF-κB. Consistently, adoptive transfer of MBP-primed T cells, but not that of NaPA-pretreated MBP-primed T cells, induced the clinical symptoms of EAE in female SJL/J mice. Furthermore, MBP-primed T cells isolated from NaPA-treated donor mice were also less efficient than MBP-primed T cells isolated from normal donor mice in inducing iNOS in microglial cells and transferring EAE to recipient mice. Interestingly, clinical symptoms of EAE were much less in mice receiving NaPA through drinking water than those without NaPA. Similar to NaPA, sodium phenylbutyrate, a chemically synthesized precursor of NaPA, also inhibited the disease process of EAE. Histological and immunocytochemical analysis showed that NaPA inhibited EAE-induced spinal cord mononuclear cell invasion and normalized iNOS, nitrotyrosine, and p65 (the RelA subunit of NF-κB) expression within the spinal cord. Taken together, our results raise the possibility that NaPA or sodium phenylbutyrate taken through drinking water or milk may reduce the observed neuroinflammation and disease process in multiple sclerosis patients.
Complement Factor C5a Mediates Renal Ischemia-Reperfusion Injury Independent from Neutrophils
Authors: de Vries Bart , Köhl Jörg , Leclercq Wouter K. G. , Wolfs Tim G. A. M. , van Bijnen Annemarie A. J. H. M. , Heeringa Peter , Buurman Wim A. 
Published: April 2014

Abstract
The complement system has been shown to mediate renal ischemia-reperfusion (I/R) injury. However, the contribution of complement factor C5a to I/R injury, in particular in the kidney, remains to be established. In this study, we investigated the impact of blocking the C5aR pathway on the inflammatory response and on the renal function in a murine model of I/R injury. First, we analyzed C5aR expression in kidneys of healthy mice. Intriguingly, we found expression on mesangial, as well as on tubular epithelial, cells. After I/R injury, C5aR expression was up-regulated in tubular epithelial cells. In addition, mRNA levels of CXC chemokines and TNF-α increased significantly and kidneys were heavily infiltrated by neutrophils. Blocking the C5aR pathway by a specific C5a receptor antagonist (C5aRA) abrogated up-regulation of CXC chemokines but not of TNF-α and reduced neutrophil infiltration by &gt;50%. Moreover, application of the C5aRA significantly reduced loss of renal function. This improvement of function was independent of the presence of neutrophils because neutrophil depletion by mAb NIMP-R14 did not affect the protective effect of C5aRA treatment. Furthermore, blocking of the C5aR pathway had no influence on renal apoptosis. These data provide evidence that C5a is crucially involved in the pathogenesis of renal I/R injury by modulation of neutrophil-dependent as well as neutrophil-independent pathways, which include the regulation of CXC chemokines but not TNF-α or apoptotic pathways.
IFN-γ Induces High Mobility Group Box 1 Protein Release Partly Through a TNF-Dependent Mechanism
Authors: Rendon-Mitchell Beatriz , Ochani Mahendar , Li Jianhua , Han Jialian , Wang Hong , Yang Huan , Susarla Seenu , Czura Christopher , Mitchell Robert A. , Chen Guoqian , Sama Andrew E. , Tracey Kevin J. , Wang Haichao 
Published: April 2014

AbstractWe recently discovered that a ubiquitous protein, high mobility group box 1 protein (HMGB1), is released by activated macrophages, and functions as a late mediator of lethal systemic inflammation. To elucidate mechanisms underlying the regulation of HMGB1 release, we examined the roles of other cytokines in induction of HMGB1 release in macrophage cell cultures. Macrophage migration inhibitory factor, macrophage-inflammatory protein 1β, and IL-6 each failed to significantly induce the release of HMGB1 even at supraphysiological levels (up to 200 ng/ml). IFN-γ, an immunoregulatory cytokine known to mediate the innate immune response, dose-dependently induced the release of HMGB1, TNF, and NO, but not other cytokines such as IL-1α, IL-1β, or IL-6. Pharmacological suppression of TNF activity with neutralizing Abs, or genetic disruption of TNF expression (TNF knockout) partially (50–60%) inhibited IFN-γ-mediated HMGB1 release. AG490, a specific inhibitor for Janus kinase 2 of the IFN-γ signaling pathway, dose-dependently attenuated IFN-γ-induced HMGB1 release. These data suggest that IFN-γ plays an important role in the regulation of HMGB1 release through a TNF- and Janus kinase 2-dependent mechanism.
Intranasal Immunotherapy Is More Effective Than Intradermal Immunotherapy for the Induction of Airway Allergen Tolerance in Th2-Sensitized Mice
Authors: Takabayashi Kenji , Libet Lev , Chisholm Dugald , Zubeldia Jose , Horner Anthony A. 
Published: April 2014

Abstract
Immunotherapy (IT) by injection more readily induces clinical tolerance to stinging insects than to respiratory allergens. However, while systemic immunization induces adaptive responses systemically, the induction of mucosal immunity generally requires local Ag exposure. Taken together, these observations suggest that the poor success rate of systemic IT for asthma could be a consequence of inadequate immune modulation in the airways. In support of this position, investigations presented in this report demonstrate that allergen IT more effectively induces airway allergen tolerance in Th2-sensitized mice, when delivered by the intranasal (i.n.) vs the intradermal (i.d.) route. Moreover, compared with native allergen, allergen immunostimulatory sequence oligodeoxynucleotide conjugate proved to be a more effective i.n. IT reagent for protecting allergic mice from airway hypersensitivity responses. Furthermore, for both native allergen and allergen immunostimulatory sequence oligodeoxynucleotide conjugate, i.n. and i.d. IT delivery were similarly effective in modulating systemic immune profiles in Th2-sensitized mice, while only i.n. IT had significant immunomodulatory activity on B and T cell responses in the airways. The present investigations may be the first to suggest that i.n. IT is more effective than i.d. IT for the treatment of asthma. Furthermore, our results suggest that modulating airway rather than systemic immunity may be the more important therapeutic target for the induction of clinical tolerance to respiratory allergens.
Viremia Control Despite Escape from a Rapid and Potent Autologous Neutralizing Antibody Response After Therapy Cessation in an HIV-1-Infected Individual
Authors: Montefiori David C. , Altfeld Marcus , Lee Paul K. , Bilska Miroslawa , Zhou Jintao , Johnston Mary N. , Gao Feng , Walker Bruce D. , Rosenberg Eric S. 
Published: April 2014

Abstract
The neutralizing Ab response after primary HIV-1 infection is delayed relative to the virus-specific CD8+ T cell response and the initial decline in plasma viremia. Because nearly all HIV-1 infections result in AIDS, it would be instructive to study cases where neutralizing Ab production commenced sooner. This was done in subject AC10, an individual treated during early infection and in whom a rapid autologous neutralizing Ab response was detected after therapy cessation as rebound viremia declined and remained below 1000 RNA copies/ml of blood for over 2.5 years. This subject’s Abs were capable of reducing the infectivity of his rebound virus by &gt;4 logs in vitro at a time when rebound viremia was down-regulated and virus-specific CD8+ T cells were minimal, suggesting that neutralizing Abs played an important role in the early control of viremia. The rebound virus did not exhibit an unusual phenotype that might explain its high sensitivity to neutralization by autologous sera. Neutralization escape occurred within 75 days and was proceeded by neutralizing Ab production to the escape variant and subsequent escape. Notably, escape was not associated with a significant rise in plasma viremia, perhaps due to increasing CD8+ T cell responses. Sequence analysis of gp160 revealed a growing number of mutations over time, suggesting ongoing viral evolution in the face of potent antiviral immune responses. We postulate that an early effective neutralizing Ab response can provide long-term clinical benefits despite neutralization escape.
IL-12 Deficiency in MRL-FaslprMice Delays Nephritis and Intrarenal IFN-γ Expression, and Diminishes Systemic Pathology
Authors: Kikawada Eriya , Lenda Deborah M. , Kelley Vicki R. 
Published: April 2014

AbstractAutoimmune disease in MRL-Faslpr mice is characterized by fatal nephritis, systemic pathology, and autoantibodies, mimicking human lupus. We previously reported that 1) intrarenal IL-12 elicits nephritis by fostering the accumulation of intrarenal IFN-γ-secreting T cells, and 2) MRL-Faslpr mice deficient in the IFN-γ receptor were spared from nephritis. Therefore, we hypothesized that eliminating IL-12 in MRL-Faslpr mice reduces IFN-γ-secreting cells and thereby prevents systemic pathology. For this purpose, we constructed an IL-12p40-deficient MRL-Faslpr(IL-12−/−) strain. We determined that glomerular and interstitial, but not perivascular, renal pathology were decreased in IL-12−/− mice vs the wild-type (WT) strain (5 mo of age). Similarly, systemic pathology (lung, lacrimal and salivary glands, skin, and lymphadenopathy) was diminished. The intrarenal accumulation of T cells (CD4+, CD8+, CD4−CD8−B220+) and macrophages was dramatically reduced in IL-12−/− MRL-Faslpr kidneys. We determined that there were fewer IFN-γ transcripts (&gt;70%) in the IL-12−/− protected kidneys compared with the WT kidneys. Similarly, cells propagated from IL-12−/− MRL-Faslpr kidneys generated substantially less IFN-γ when stimulated with IL-12 and IL-18 compared with those from WT kidneys, and we detected fewer CD8 and B220 T cells producing IFN-γ in these IL-12−/− MRL-Faslpr kidneys. Of note, survival was modestly extended in the IL-12−/− MRL-Faslpr mice. While lung and lacrimal and salivary gland pathology remained reduced in moribund IL-12−/− MRL-Faslpr mice, renal pathology and IFN-γ expression were equivalent to those in the WT strain. Thus, we suggest that IL-12 is a therapeutic target for multiple tissues in lupus; however blocking IL-12 alone is not sufficient to confer enduring protection from lupus nephritis.
Cutting Edge: CD8+ Effector T Cells Reject Tumors by Direct Antigen Recognition but Indirect Action on Host Cells
Authors: Schüler Thomas , Blankenstein Thomas 
Published: April 2014

AbstractCD8+ effector T cells recognize malignant cells by monitoring their surface for the presence of tumor-derived peptides bound to MHC class I molecules. In addition, tumor-derived Ags can be cross-presented to CD8+ effector T cells by APCs. IFN-γ production by CD8+ T cells is often critical for tumor rejection. However, it remained unclear whether 1) CD8+ T cells secrete IFN-γ in response to Ag recognition on tumor cells or APCs and 2) whether IFN-γ mediates its antitumor effect by acting on host or tumor cells. We show in this study that CD8+ effector T cells can reject tumors in bone marrow-chimeric mice incapable of cross-presenting Ag by bone marrow-derived APCs and that tumor rejection required host cells to express IFN-γR. Together, CD8+ effector T cells recognize Ag directly on tumor cells, and this recognition is sufficient to reject tumors by IFN-γ acting on host cells.
Cutting Edge: Roles of Toll-Like Receptor 4 and IL-23 in IL-17 Expression in Response toKlebsiella pneumoniaeInfection
Authors: Happel Kyle I. , Zheng Mingquan , Young Erana , Quinton Lee J. , Lockhart Euan , Ramsay Alistair J. , Shellito Judd E. , Schurr Jill R. , Bagby Gregory J. , Nelson Steve , Kolls Jay K. 
Published: April 2014

AbstractLocal production of IL-17 is a significant factor in effective host defense against Gram-negative bacteria. However, the proximal events mediating IL-17 elaboration by T cells remain unclear. In this study, we show in vivo that intact Toll-like receptor 4 signaling in the lung is required for induction of both the p19 transcript of IL-23 and IL-17 protein elaboration in response to Klebsiella pneumoniae. Although IL-17 is widely considered a CD4+ T cell product, we also demonstrate significant in vitro IL-17 production by CD8+ T cells after culture in medium from dendritic cells exposed to these bacteria. The dominant portion of this IL-17-inducing activity for both CD4+ and CD8+ T cells is IL-23. These data demonstrate the critical signaling pathway for IL-17 induction in the host response to Gram-negative pulmonary infection and suggest a direct role for IL-23 in CD8+ T cell IL-17 production.
Cutting Edge: Conventional CD8α+ Dendritic Cells Are Preferentially Involved in CTL Priming After Footpad Infection with Herpes Simplex Virus-1
Authors: Smith Christopher M. , Belz Gabrielle T. , Wilson Nicholas S. , Villadangos Jose A. , Shortman Ken , Carbone Francis R. , Heath William R. 
Published: April 2014

Abstract
CTL play a major role in immunity to HSV type 1, but little is known about the priming process. In this study, we have examined the class I-restricted presentation of an immunodominant determinant from HSV-1 glycoprotein B after footpad infection. We have found that the only cell types capable of presenting this determinant in draining popliteal lymph nodes within the first 3 days after infection are the CD11c+CD8α+CD45RA− dendritic cells. Given that such class I-restricted presentation is essential for CTL priming, this implies that these conventional CD8α+ dendritic cells are the key subset involved in CTL immunity to this virus.
A Pyrazole Derivative, YM-58483, Potently Inhibits Store-Operated Sustained Ca2+ Influx and IL-2 Production in T Lymphocytes
Authors: Ishikawa Jun , Ohga Keiko , Yoshino Taiji , Takezawa Ryuichi , Ichikawa Atsushi , Kubota Hirokazu , Yamada Toshimitsu 
Published: April 2014

Abstract
In nonexcitable cells, Ca2+ entry is mediated predominantly through the store depletion-dependent Ca2+ channels called store-operated Ca2+ (SOC) or Ca2+ release-activated Ca2+ channels. YM-58483, a pyrazole derivative, inhibited an anti-CD3 mAb-induced sustained Ca2+ influx in acute T cell leukemia, Jurkat cells. But it did not affect an anti-CD3 mAb-induced transient intracellular Ca2+ increase in Ca2+-free medium, nor anti-CD3 mAb-induced phosphorylation of phospholipase Cγ1. It was suggested that YM-58483 inhibited Ca2+ influx through SOC channels without affecting the TCR signal transduction cascade. Furthermore, YM-58483 inhibited thapsigargin-induced sustained Ca2+ influx with an IC50 value of 100 nM without affecting membrane potential. YM-58483 inhibited by 30-fold the Ca2+ influx through SOC channels compared with voltage-operated Ca2+ channels, while econazole inhibited both SOC channels and voltage-operated Ca2+ channels with an equivalent range of IC50 values. YM-58483 potently inhibited IL-2 production and NF-AT-driven promoter activity, but not AP-1-driven promoter activity in Jurkat cells. Moreover, this compound inhibited delayed-type hypersensitivity in mice with an ED50 of 1.1 mg/kg. Therefore, we concluded that YM-58483 was a novel store-operated Ca2+ entry blocker and a potent immunomodulator, and could be useful for the treatment of autoimmune diseases and chronic inflammation. Furthermore, YM-58483 would be a candidate for the study of capacitative Ca2+ entry mechanisms through SOC/CRAC channels and for identification of putative Ca2+ channel genes.