bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of IL-18 to Th1 Response and Host Defense Against Infection by Mycobacterium tuberculosis: A Comparative Study with IL-12p40
Authors: Kinjo Yuki , Kawakami Kazuyoshi , Uezu Kaori , Yara Satomi , Miyagi Kazuya , Koguchi Yoshinobu , Hoshino Tomoaki , Okamoto Masaki , Kawase Yusuke , Yokota Koichi , Yoshino Kohichiro , Takeda Kiyoshi , Akira Shizuo , Saito Atsushi 
Published: April 2014

Abstract
The present study was conducted to critically determine the protective role of IL-18 in host response to Mycobacterium tuberculosis infection. IL-18-deficient (knockout (KO)) mice were slightly more prone to this infection than wild-type (WT) mice. Sensitivity of IL-12p40KO mice was lower than that of IL-12p40/IL-18 double KO mice. IFN-γ production caused by the infection was significantly attenuated in IL-18KO mice compared with WT mice, as indicated by reduction in the levels of this cytokine in sera, spleen, lung, and liver, and its synthesis by spleen cells restimulated with purified protein derivatives. Serum IL-12p40 level postinfection and its production by peritoneal exudate cells stimulated with live bacilli were also significantly lower in IL-18KO mice than WT mice, suggesting that attenuated production of IFN-γ was secondary to reduction of IL-12 synthesis. However, this was not likely the case, because administration of excess IL-12 did not restore the reduced IFN-γ production in IL-18KO mice. In further studies, IL-18 transgenic mice were more resistant to the infection than control littermate mice, and serum IFN-γ level and its production by restimulated spleen cells were increased in the former mice. Taken together, our results indicate that IL-18 plays an important role in Th1 response and host defense against M. tuberculosis infection although the contribution was not as profound as that of IL-12p40.
The Role of Proinflammatory Cytokines in Wasting Disease During Lymphocytic Choriomeningitis Virus Infection
Authors: Kamperschroer Cris , Quinn Daniel G. 
Published: April 2014

Abstract
Infection with pathogens often leads to loss of body weight, but the cause of weight loss during infection is poorly understood. We used the infection of mice with lymphocytic choriomeningitis virus (LCMV) as a model to study how pathogens induce weight loss. If LCMV is introduced into the CNS of CTL-deficient mice, the immune response against the virus leads to a severe weight loss called wasting disease. We planned to determine what components of this antiviral immune response mediate wasting disease. By adoptive transfer, we show that CD4 T cells activated by LCMV infection are sufficient to cause wasting disease. We examined the role of cytokines in LCMV-induced wasting disease using mice lacking specific cytokines or cytokine receptors. Results of adoptive transfer experiments suggest that TNF-α is not involved in LCMV-induced wasting disease and show that IFN-γ contributes to the disease. Consistent with a role for IFN-γ in wasting, we find that IFN-γ is necessary for LCMV-specific CD4 T cell responses in the CNS, most likely because it is required to induce MHC class II expression. Our data also indicate that IL-1 is required for LCMV-induced wasting and that IL-6 contributes to the wasting disease. Additionally, our results identify α-melanocyte-stimulating hormone as a potential mediator of the disease. Overall, this work defines the critical role of virus-primed CD4 T cells and of proinflammatory cytokines in the pathogenesis of wasting disease induced by LCMV infection.
Type I IFN as a Natural Adjuvant for a Protective Immune Response: Lessons from the Influenza Vaccine Model
Authors: Proietti Enrico , Bracci Laura , Puzelli Simona , Di Pucchio Tiziana , Sestili Paola , De Vincenzi Enrico , Venditti Massimo , Capone Imerio , Seif Isabelle , De Maeyer Edward , Tough David , Donatelli Isabella , Belardelli Filippo 
Published: April 2014

Abstract
The identification of natural adjuvants capable of selectively promoting an efficient immune response against infectious agents would represent an important advance in immunology, with direct implications for vaccine development, whose progress is generally hampered by the difficulties in defining powerful synthetic adjuvants suitable for clinical use. Here, we demonstrate that endogenous type I IFN is necessary for the Th1 type of immune response induced by typical adjuvants in mice and that IFN itself is an unexpectedly powerful adjuvant when administered with the human influenza vaccine, for inducing IgG2a and IgA production and conferring protection from virus challenge. The finding that these cytokines, currently used in patients, are necessary for full expression of adjuvant activity and are sufficient for the generation of a protective immune response opens new perspectives in understanding the basis of immunity and in vaccine development.
The Epistatic Interrelationships of IL-1, IL-1 Receptor Antagonist, and the Type I IL-1 Receptor
Authors: Irikura Vera M. , Lagraoui Mouna , Hirsh David 
Published: April 2014

Abstract
Mice lacking the gene for the IL-1R antagonist (IL-1ra) show abnormal development and homeostasis as well as altered responses to infectious and inflammatory stimuli. A reduction in the level of IL-1 signaling, either by deletion of the receptor or increased expression of IL-1ra, does not affect development or homeostasis, but does alter immune responses. In this study we use genetic epistasis to investigate the interdependence of selected genes in the IL-1 family in the regulation of these developmental and immunological processes. Deletion of the gene encoding the type I IL-1R (IL-1RI) is epistatic to deletion of the IL-1ra gene. Therefore, all functions of IL-1ra depend upon the presence of a functional receptor; there is no other target. Similarly, overexpression of the mRNA encoding the secreted form of IL-1ra is epistatic to deletion of the receptor antagonist, leaving the role of the intracellular splice variants of IL-1ra unknown. The abnormal development of IL-1ra-deficient mice is probably due to chronic overstimulation of the proinflammatory pathway via IL-1, but a clear single pathological defect is not apparent. These results support the model that the only essential function of IL-1ra in both health and disease is competitive inhibition of the IL-1RI.
Differential Glucocorticoid Enhancement of the Cytokine-Driven Transcriptional Activation of the Human Acute Phase Serum Amyloid A Genes, SAA1 and SAA2
Authors: Thorn Caroline F. , Whitehead Alexander S. 
Published: April 2014

Abstract
The human acute phase serum amyloid A (A-SAA) genes, SAA1 and SAA2, have a high degree of sequence identity that extends ∼450 bp upstream of their transcription start sites. Each promoter contains analogously positioned functional binding sites for the transcription factors NF-κB and NF-IL6. In human HepG2 hepatoma cells transfected with SAA promoter luciferase reporter constructs, administration of IL-1 and IL-6, singly or in combination, induced SAA1 and SAA2 transcriptional readouts that were qualitatively indistinguishable. However, under induced conditions, the SAA2 promoter had a significant quantitative transcriptional advantage over the SAA1 promoter. The application of the synthetic glucocorticoid dexamethasone in the context of cytokine stimulation enhanced the transcriptional activity of the SAA1, but not the SAA2, promoter such that readout from the former became equivalent to that from the latter. A putative glucocorticoid response element (GRE) is present (between residues −208 and −194) only in the SAA1 gene; a similar sequence in the corresponding region of the SAA2 gene is disrupted by a nine-residue insertion. The SAA1 GRE was shown to be functionally active and the SAA2 disrupted GRE was shown to be functionally inactive in experiments using reporter constructs carrying SAA1 and SAA2 promoters that had been modified by site-specific mutagenesis. Quantitative analysis of transcript-specific RT-PCR products, derived from SAA1 and SAA2 mRNAs after treatment of HepG2 cells with cytokines in the presence or absence of dexamethasone, confirmed that the endogenous SAA1 gene has a cytokine-driven transcriptional disadvantage that is superseded by a marginal transcriptional advantage when glucocorticoids are present.
Cooperative Effects of Th2 Cytokines and Allergen on Normal and Asthmatic Bronchial Epithelial Cells
Authors: Lordan James L. , Bucchieri Fabio , Richter Audrey , Konstantinidis Athanassias , Holloway John W. , Thornber Matthew , Puddicombe Sarah M. , Buchanan Diana , Wilson Susan J. , Djukanović Ratko , Holgate Stephen T. , Davies Donna E. 
Published: April 2014

Abstract
In sensitized individuals, exposure to allergens such as Dermatophagoides pteronyssinus (Der p) causes Th2 polarization and release of cytokines, including IL-4 and IL-13. Because Der p extracts also have direct effects on epithelial cells, we hypothesized that allergen augments the effects of Th2 cytokines by promoting mediator release from the bronchial epithelium in allergic asthma. To test our hypothesis, primary bronchial epithelial cultures were grown from bronchial brushings of normal and atopic asthmatic subjects. RT-PCR showed that each culture expressed IL-4Rα, common γ-chain, and IL-13Rα1, as well as IL-13Rα2, which negatively regulates IL-13 signaling; FACS analysis confirmed IL-13Rα2 protein expression. Exposure of epithelial cultures to either Der p extracts, TNF-α, IL-4, or IL-13 enhanced GM-CSF and IL-8 release, and this was partially suppressible by corticosteroids. Simultaneous exposure of the epithelial cultures to IL-4 or IL-13 together with Der p resulted in a further increase in cytokine release, which was at least additive. Release of TGF-α was also increased by TNF-α and combinations of IL-4, IL-13, and Der p; however, this stimulation was only significant in the asthma-derived cultures. These data suggest that, in an allergic environment, Th2 cytokines and allergen have the potential to sustain airway inflammation through a cooperative effect on cytokine release by the bronchial epithelium. Our novel finding that IL-4, IL-13, and allergen enhance release of TGF-α, a ligand for the epidermal growth factor receptor that stimulates fibroblast proliferation and goblet cell differentiation, provides a potential link between allergen exposure, Th2 cytokines, and airway remodelling in asthma.
Impaired IFN-γ-Dependent Inflammatory Responses in Human Keratinocytes Overexpressing the Suppressor of Cytokine Signaling 1
Authors: Federici Monica , Giustizieri Maria Laura , Scarponi Claudia , Girolomoni Giampiero , Albanesi Cristina 
Published: April 2014

Abstract
Keratinocytes contribute relevantly to the pathogenesis of inflammatory skin diseases by expressing a variety of proinflammatory molecules, with T cell-derived IFN-γ being the most potent keratinocyte activator. Suppressor of cytokine signaling (SOCS)1 and SOCS3 are negative regulators of IFN-γ signaling and are induced in many cell types by IFN-γ itself or by other cytokines. We show in this work that SOCS1, SOCS2, SOCS3, and cytokine-inducible SH2-containing protein mRNA were up-regulated by IFN-γ in normal human keratinocytes, whereas only SOCS1 or SOCS1 and cytokine-inducible SH2-containing protein were induced by TNF-α or IL-4, respectively. SOCS1, SOCS2, and SOCS3 proteins were undetectable in healthy skin and highly expressed in the epidermis of psoriasis and allergic contact dermatitis, but were only weakly expressed in atopic dermatitis skin. In keratinocytes transiently transfected with SOCS1 or SOCS3 the IFN-γ-induced transactivation of an IFN-γ-responsive reporter gene was markedly inhibited. SOCS1 and SOCS3 overexpression in keratinocyte stable clones inhibited IFN-γ-induced phosphorylation of IFN-γRα and activation of STAT1 and STAT3. Furthermore, SOCS1 and, to a lesser extent, SOCS3 reduced membrane expression of ICAM-1 and HLA-DR, and release of IFN-γ-inducible protein-10, monokine induced by IFN-γ, and monocyte chemoattractant protein-1 by keratinocyte clones promoted by IFN-γ. SOCS1-expressing keratinocytes showed constitutively higher, but not IFN-γ-inducible, IL-8 levels compared with SOCS2 and SOCS3 clones, and were resistant to IFN-γ-mediated growth inhibition. Targeting keratinocyte SOCS1 may represent a novel therapeutic approach to IFN-γ-dependent skin diseases.
Proinflammatory Cytokine IL-1β Promotes Tumor Growth of Lewis Lung Carcinoma by Induction of Angiogenic Factors: In Vivo Analysis of Tumor-Stromal Interaction
Authors: Saijo Yasuo , Tanaka Masashi , Miki Makoto , Usui Kazuhiro , Suzuki Takuji , Maemondo Makoto , Hong Xin , Tazawa Ryushi , Kikuchi Toshiaki , Matsushima Kouji , Nukiwa Toshihiro 
Published: April 2014

Abstract
Inflammatory conditions are associated with tumor development. IL-1β is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1β in tumor growth in vivo, we transduced the retroviral vector coding human IL-1β gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1β) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1β grew faster (240%, day 18, vs null-vector control LLC/neo; p &lt; 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p &lt; 0.05), whereas LLC/IL-1β cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1β cells secreted 2-fold the amount of vascular endothelial growth factor and &gt;10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1β itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1β cells also contained a &gt;4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1β tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1β cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1β cells in vivo. These results indicated that secreting IL-1β into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.
Cutting Edge: Molecular Portrait of Human Autoimmune Disease
Authors: Maas Kevin , Chan Sanny , Parker Joel , Slater Angela , Moore Jason , Olsen Nancy , Aune Thomas M. 
Published: April 2014

Abstract
Autoimmune diseases affect 3–5% of the population, are mediated by the immune response to self-Ags, and are characterized by the site of tissue destruction. We compared expression levels of &gt;4,000 genes in PBMC of control individuals before and after immunization to those of individuals with four distinct autoimmune diseases. The gene expression profile of the normal immune response exhibits coordinate changes in expression of genes with related functions over time. In contrast, each individual from all autoimmune diseases displays a similar gene expression profile unrelated to the pattern of the immunized group. To our surprise, genes with a distinct expression pattern in autoimmunity are not necessarily “immune response” genes, but are genes that encode proteins involved in apoptosis, cell cycle progression, cell differentiation, and cell migration.
Analysis of the Innate and Adaptive Phases of Allograft Rejection by Cluster Analysis of Transcriptional Profiles
Authors: Christopher Kenneth , Mueller Thomas F. , Ma Chunyan , Liang Yurong , Perkins David L. 
Published: April 2014

AbstractBoth clinical and experimental observations suggest that allograft rejection is a complex process with multiple components that are, at least partially, functionally redundant. Studies using graft recipients deficient in various genes including chemokines, cytokines, and other immune-associated genes frequently produce a phenotype of delayed, but not indefinitely prevented, rejection. Only a small subset of genetic deletions (for example, TCRα or β, MHC I and II, B7-1 and B7-2, and recombinase-activating gene) permit permanent graft acceptance suggesting that rejection is orchestrated by a complex network of interrelated inflammatory and immune responses. To investigate this complex process, we have used oligonucleotide microarrays to generate quantitative mRNA expression profiles following transplantation. Patterns of gene expression were confirmed with real-time PCR data. Hierarchical clustering algorithms clearly differentiated the early and late phases of rejection. Self-organizing maps identified clusters of coordinately regulated genes. Genes up-regulated during the early phase included genes with prior biological functions associated with ischemia, injury, and Ag-independent innate immunity, whereas genes up-regulated in the late phase were enriched for genes associated with adaptive immunity.
Identification of HLA-A*0201-Restricted T Cell Epitopes Derived from the Novel Overexpressed Tumor Antigen Calcium-Activated Chloride Channel 2
Authors: Konopitzky Renate , König Ulrich , Meyer Ralf G. , Sommergruber Wolfgang , Wölfel Thomas , Schweighoffer Tamás 
Published: April 2014

Abstract
Vaccination against tumor Ags may become a promising treatment modality especially in cancer types where other therapeutic approaches fail. However, diversity of tumors requires that a multitude of Ags become available. Differential expression in normal vs cancerous tissues, both at the mRNA and the protein level, may identify Ag candidates. We have previously compared transcripts from squamous cell lung cancer and normal lung tissue using differential display analysis, and found a transcript that was overexpressed in malignant cells and was identical with the calcium-activated chloride channel 2 (CLCA2) gene. We have now selected HLA-A2-restricted peptides from CLCA2, and have generated T cell lines against the CLCA2-derived KLLGNCLPTV, LLGNCLPTV, and SLQALKVTV peptides using in vitro priming. Specificity of T cells was ascertained in ELISPOT assays. The primed T cells also recognized allogeneic tumor cells in an Ag-specific and HLA-restricted fashion. Moreover, peptide LLGNCLPTV was also independently recognized by CD8+ T cells expanded from pancreatic carcinoma/T cell cocultures. CLCA2-specific CD8+ T cells were absent from the peripheral blood of healthy donors. These data indicate that an immune response can be induced against CLCA2, which thus may become an important Ag for anti-tumor vaccination approaches.
2B4 Is Constitutively Associated with Linker for the Activation of T Cells in Glycolipid-Enriched Microdomains: Properties Required for 2B4 Lytic Function
Authors: Klem Jennifer , Verrett Pamela C. , Kumar Vinay , Schatzle John D. 
Published: April 2014

Abstract
2B4 is a receptor belonging to the Ig superfamily and is found on all murine NK cells as well as a small subset of T cells. Previous studies have found that cross-linking of the 2B4 receptor results in both increased cytotoxicity and IFN-γ secretion. We have discovered that 2B4 from transfected NK and T cell lines, as well as from primary murine cells, coimmunoprecipitates with the phosphoprotein linker for the activation of T cells (LAT), which is essential for TCR-mediated signaling. This association is independent of both 2B4 phosphorylation and the cytoplasmic tail of 2B4. We have found that, along with LAT, 2B4 is constitutively located in glycolipid-enriched microdomains of the plasma membrane. In fact, 2B4 appears to associate with LAT only when it localizes to glycolipid-enriched microdomains. This localization of 2B4 occurs due to a CxC cysteine motif found in the transmembrane region, as determined by mutagenesis studies. 2B4-mediated cytotoxicity is defective in the absence of LAT, indicating that LAT is a required intermediate for 2B4 signal transduction. However, we have also shown that LAT association alone is not sufficient for maximal 2B4 activation.
Identification of Naturally Processed CD4 T Cell Epitopes from the Prostate-Specific Antigen Kallikrein 4 Using Peptide-Based In Vitro Stimulation
Authors: Hural John A. , Friedman Rachel S. , McNabb Andria , Steen Sean S. , Henderson Robert A. , Kalos Michael 
Published: April 2014

Abstract
Kallikrein (KLK)4 is a recently described member of the tissue kallikrein gene family that is specifically expressed in normal and prostate tumor tissues. The tissue-specific expression profile of this molecule suggests that it might be useful as a vaccine candidate against prostate cancer. To examine the presence of CD4 T cells specific for KLK4 in PBMC of normal individuals, a peptide-based in vitro stimulation protocol was developed that uses overlapping KLK4-derived peptides spanning the majority of the KLK4 protein. Using this methodology, three naturally processed CD4 epitopes derived from the KLK4 sequence are identified. These epitopes are restricted by HLA-DRB1*0404, HLA-DRB1*0701, and HLA-DPB1*0401 class II alleles. CD4 T cell clones specific for these epitopes are shown to efficiently and specifically recognize both recombinant KLK4 protein and lysates from prostate tumor cell lines virally infected to express KLK4. CD4 T cells specific for these KLK4 epitopes are shown to exist in PBMC from multiple male donors that express the relevant class II alleles, indicating that a CD4 T cell repertoire specific for KLK4 is present and potentially expandable in prostate cancer patients. The demonstration that KLK4-specific CD4 T cells exist in the peripheral circulation of normal male donors and the identification of naturally processed KLK4-derived CD4 T cell epitopes support the use of KLK4 in whole gene-, protein-, or peptide-based vaccine strategies against prostate cancer. Furthermore, the identification of naturally processed KLK4-derived epitopes provides valuable tools for monitoring preexisting and vaccine-induced responses to this molecule.