bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunomodulatory effects of CMDB, the component of Cordyceps militaris mycelium, by the enhanced production of cytokines in macrophages (B64)
Authors: Kim Kyungjae , Kim Hyunyul , Han Shinha , Kim Kwanghee , Kwon Jeunghak , Lee Seungjeong 
Published: January 2023

Abstract
Cordyceps militaris (CM) have been reported to modify the immune and inflammatory responses both in vivo and in vitro. Macrophages play important roles in the innate immunity through the phagocytosis of antigens. This study examined the effects of CM on the activation of murine macrophage RAW264.7 cells. The filtered components of the draff broth (DB) cultured with mycelium of CM, CMDB, CMDBW, CMDB5P, CMDB25P, were purified by propyl alcohol extraction and HP 20 column chromatography. All the components of CM produced significant amounts of nitric oxide (NO). In particular, CMDB produced much more NO in RAW264.7 cells and primary macrophages than the other fractions of CM. CMDB increased significantly the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 dose-dependently in RAW264.7 cells. To examine whether the CMDB effects on cytokine production were attributable to its influence on the expression of mRNAs, semi-quantitative RT-PCR experiments were performed for the transcripts. Examination of the gene expression level showed that the enhanced production of cytokines was correlated with the up-regulation of i-NOS expression, cycloxygenase (COX)-2 expression, IL-1β and IL-6 expression, and TNF-α gene expression. Western blot analysis also confirmed that CMDB enhances the expression level of these cytokines. These results suggest that CMDB has immunostimulatory effects on macrophages through the enhanced production of cytokines.
Homing molecule expression on skin tropic herpes simplex virus type-2 (HSV-2)-specific CD8+ T-cells: role of fucosyltransferase-VII (B68)
Authors: Hensel Michael , Caka Selin E , Wald Anna , Koelle David M 
Published: January 2023

Abstract
Homing of pathogen specific T-cells is an important component of the host immune response. HSV-2-specific T-cells express high levels of cutaneous lymphocyte-associated antigen (CLA) and the related E-selectin ligand (ESL). Control CMV- or EBV-specific T-cells express low levels of CLA/ESL. CLA/ESL expression and lymphocyte homing to skin are dependent on fucosyltransferases-IV and –VII (FT-IV and FT-VII). We used real-time PCR to compare levels of FT-VII mRNA in isolated CD8-pos T-cells specific for HSV-2, EBV, and CMV from un-manipulated blood using tetramer (tet) staining and cell sorting. Within a group of subjects, circulating HSV-2-specific cells had higher levels of FT-VII mRNA than did EBV-specific cells (p=0.02) but not CMV-specific cells (p=0.29). Using within-subject comparisons, HSV-2 tet-pos cells had higher levels of FT-VII mRNA than did CD8-pos tet-neg bystander cells (p=0.02). In contrast, FT-VII mRNA levels within EBV or CMV tet-pos cells were not higher than levels in CD8 tet-neg bystanders (p=0.31 and p=0.44, respectively). Ongoing studies using HSV-2-specific cells to study skin-homing at the protein and mRNA levels are in progress.
Research support provided by: STD/AIDS Research Training Grant NIHT32 AI07140 and UW Royalty Research Fund 65-0875
Activation and Nuclear translocation of p65 NF-kappaB are sufficient for VCAM-1, but insufficient for ICAM-1, expression in TNF-stimulated primary smooth muscle cells: differential requirement for PARP-1 expression and interaction (B73)
Authors: Boulares Hamid , Suzuki Yasuhiro , Zerfaoui Mourad , Naura Amarjit , Hans Chetan , Nichols C 
Published: January 2023

Abstract
Although nuclear translocation of NF-κB and subsequent binding to promoters of ICAM-1 and VCAM-1 have been shown to be decisive for their expression, a number of discrepancies in the expression pattern of these adhesion molecules have been reported in cell culture systems and in disease settings including atherosclerosis, asthma, and auto-immune diseases. Here we show that while p65 NF-κB nuclear translocation in TNF-treated smooth muscle cells (SMC) was sufficient for the expression of VCAM-1, ICAM-1 expression required the expression of PARP-1. I-κBα phosphorylation and subsequent degradation were virtually identical in both TNF-treated wild type and PARP-1−/− SMC. VCAM-1 expression in TNF-treated PARP-1−/− SMC was confirmed to be NF-κB-dependent given that PDTC inhibited its expression. The expression of VCAM-1 and ICAM-1 were associated with a transient interaction between PARP-1 and p65 NF-κB when examined in the airway epithelial cell line A549. Such interaction was confirmed using fluorescence resonance energy transfer (FRET) assay. Protein acetylation activity, mediated by p300/CBP, was required for VCAM-1 and ICAM-1 expression in TNF-treated SMC, however, interaction of PARP-1 with p300 was not required for VCAM-1 expression. These findings indicate that p65 NF-κB translocation can be in some situations insufficient for some genes (e.g. ICAM-1) yet in the same time can induce the expression of others (e.g. VCAM-1), thus providing a new concept on the role of NF-κB in driving its target genes. Further, the data suggest a differential requirement for PARP-1 expression in inflammatory processes.
Support: NIH-HL072889 and 1P20RR18766 to HB.
Signal transduction blockade with imatinib mesylate prevents and treats autoimmune arthritis (B76)
Authors: Paniagua Ricardo , Sharpe Orr , Ho Peggy , Chan Steven , Chang Anna , Tomooka Beren , Lee David , Genovese Mark , Utz Paul , Steinman Lawrence , Robinson William 
Published: January 2023

Abstract
For over two decades researchers have speculated on the potential use of kinase inhibitors to treat autoimmune diseases. To date, investigations of kinase inhibitors have been largely limited by low therapeutic indices that result in unacceptable toxicity profiles. We show that imatinib mesylate, a tyrosine kinase inhibitor FDA-approved to treat chronic myeloid leukemia and gastrointestinal stromal tumors, has the potential to provide benefit for autoimmune diseases such as rheumatoid arthritis (RA). We demonstrate that imatinib, at a dose equivalent to 200–400mg/day in humans, prevents murine autoimmune arthritis and treats established disease. We further show that submicromolar imatinib concentrations inhibit tyrosine kinases and cellular responses that are central to RA pathogenesis, including PDGF-mediated proliferation of fibroblast-like synoviocytes, c-Fms activation and macrophage production of TNF-alpha, c-Kit-mediated mast cell release of proinflammatory cytokines, and B cell immunoglobulin production. Inhibition of tyrosine kinase pathways by imatinib represents a potent and promising therapeutic approach to treat RA and other autoimmune diseases.
Avidity of CD8 T-cells sharpens immunodominance. (B9)
Authors: Dzutsev Amiran , Belyakov Igor , Isakov Dmitry , Margulies David , Berzofsky Jay 
Published: January 2023

Abstract
In the course of viral infection, the immune system exploits only a fraction of the available CTL repertoire and focuses on a few of a myriad of potentially antigenic peptides. This phenomenon, known as immunodominance, depends on a number of factors, including antigen processing and transport, MHC binding, competition for antigen presenting cells, availability of the CD8 T-cell repertoire and other mechanisms that function largely by restricting the immune response. Here we elucidate a novel mechanism that increases the immunodominance of the epitope rather by enhancing the immune response. Using a peptide-specific MHC-restricted monoclonal antibody and functional assays of CTL activation, we show that T cells with high avidity for the immunodominant, H-2Dd-restricted, P18-I10 epitope expand rapidly following immunization, and this expansion in turn determines the level of the P18-I10 epitope immunodominance. This proliferation has little dependence on the number of MHC-peptide complexes. Since most self-reactive T-cells of high avidity are depleted in the thymus, the selection of immunodominant epitopes based on the expansion of high avidity T-cells in the periphery avoids the potential for autoimmunity.
Note on the Quantitative Relations of Antigen and Antibody in Agglutination and Precipitation Reactions
Authors: Zinsser Hans 
Published: January 2023

Abstract
One of the things that has puzzled bacteriologists and has been particularly difficult to harmonize with our conception of the unity of the sensitizers giving the different antibody reactions with one and the same antigen has been the fact that in doing agglutination reactions against bacteria it has been possible to dilute the serum often several thousand times before extinction of the reaction, whereas in doing precipitation reactions the antigen can be diluted several thousand times, but if the serum is diluted its reaction fades out, usually at dilutions of 1:10, rarely extending beyond dilutions of 1:50.
The explanation for this phenomenon seems relatively simple if one considers it from the point of view of the mechanics of flocculation. It is likely that bacterial agglutination by a specific antiserum takes place as follows: The antibody, which is inseparable from certain globulin fractions of the serum and, therefore,—physically considered—is globulin, coats the exposed particles, the coating taking place specifically by reason of chemical affinities between this antibody globulin and the antigen.
An intrinsic role for the alternative NF-kappa B pathway in the T-cell response to virus (35.21)
Authors: Rowe Alexander M , Murray Susan E. , Parker David C 
Published: January 2023

Abstract
Regulation of NF-κB mediated signaling is controlled by two systems: the classical pathway and the alternative pathway. The alternative pathway refers to the processing of p100 to p52 regulated by an enzyme called NF-κB inducing kinase (NIK), and is essential for the normal function of B-cells, macrophages, and dendritic cells; however, little is known about its function in T-cells. Preliminary experiments determined that activation of the alternative pathway is necessary for CD4 mediated graft versus host disease. Based on those findings, we hypothesized that the broader T-cell response to a viral infection is also dependent on the alternative NF-κB pathway. Because of the dominant effects of deficiencies in the alternative pathway on B-cells, macrophages and dendritic cells, we could not discretely assess the T-cell response to pathogen in alternative pathway mutants. Therefore, we generated mixed bone marrow (BM) chimeras using BM from wild-type mice and alymphoplasia (aly) mice that lack a functional NIK protein or BM from p100 knockout mice. In these chimeras, 15-20% of the T-cells, less than 2% of the B-cells and less than 2% surveyed myeloid cells, possessed the mutant genotype. This allowed us to assess the function of T-cells lacking the alternative pathway in an otherwise normal immune system. Chimeras were infected with lymphocytic choriomeningitis virus (LCMV) and the immune response was analyzed 8 days post-infection. The percent of responding CD8 and CD4 T-cells was significantly reduced among aly/aly and p100-/- populations compared to wild-type cells, as measured by the percent of IFNγ positive cells following ex vivo stimulation with LCMV peptides and activation marker expression. These data demonstrate a T-cell intrinsic role for the alternative NF-κB pathway in the immune response to a viral infection.
A single-chain MHC-class I system to investigate the role of non-stimulatory peptides in T-cell recognition (35.39)
Authors: Hoerter John , Ampudia Jeanette , Yachi Pia , Connolly Janet , Hansen Ted , Gould Keith , Gascoigne Nicholas 
Published: January 2023

Abstract
Recent work has demonstrated that endogenous or non-stimulatory peptides can enhance T-cell recognition, a finding that is unexplained by the classical model of CD8, TCR, and MHC interaction. To investigate this phenomenon, we have developed a tetracycline-inducible CHO cell system where cognate single-chain MHC-peptide is expressed at low levels and non-stimulatory single-chain MHC-peptide is constitutively expressed. Mutations in the CD8 binding site of stimulatory or non-stimulatory MHCp enable us to distinguish between different binding models in this system. Preliminary results indicate that CD8 binding to the non-stimulatory MHC is necessary for efficient activation.
Supported by NIH R01 GM065230
CD3 molecules in a conformational equilibrium that is altered by TCR engagement (35.41)
Authors: Gil Diana , Kruger Travis , de la Cruz Javier 
Published: January 2023

Abstract
Previously we and others observed that the signaling module of the TCR, the CD3 complex, undergoes a conformational change at the level of its cytoplasmic tails when T cells are stimulated. At that time, we interpreted this data as proof that antigen recognition modifies the conformation of CD3 as part of the receptor triggering mechanism. In absence of specific structural information, the induced conformation has been referred to as "open CD3". Here we present new evidence that thymocytes display detectable amounts of "open CD3" even in the absence of antigenic stimulation. However, treatment of thymocytes with stimulatory anti-CD3 antibodies significantly increases the amount of "open CD3". We conclude that ligand binding causes many CD3 molecules to adopt the "open CD3" conformation. We propose that CD3 is expressed in an equilibrium between two distinguishable conformations, which may reflect "on" and "off" states that are perturbed by TCR engagement. The accumulation of a certain level of "open CD3" might trigger T cell activation.
Research support: Diana Gil, Travis Kruger and Javier de la Cruz were supported with start-up funds from the Mayo Foundation.
Positive effects of the middle layer of Phyllostachys nigra var. henonis (PN), Bambusae Calulis in Taeniam, on asthma murine model through down-regulated ICAM-1 of BMMC (36.12)
Authors: Ra Jehyeon , Lee Sanggon , Ahn Hyunjong , Kim Jinju 
Published: January 2023

Abstract
The middle layer of Phyllostachys nigra var. henonis (PN), Bambusae Calulis in Taeniam, has been used for cough and sputum for a long time. Cough is one of the major symptoms of asthma. However, there were few of scientific investigation about PN. To investigate the positive effect of PN on asthma, we measured the production of IL-4 of bronchoalveolar lavage fluid (BalF), Immunoglobulin E (IgE) level of serum and immune cell infiltration at lung tissue by HE stain in ovalbumin (OVA) induced asthma murine model (Balb/C, female, 6 weeks). In asthma model, there was IL-4 of BalF decreased by PN, however, it was not significantly. The IgE induced by OVA in serum significantly decreased by PN (40 mg/kg). Furthermore, we observed the decrease of immune cell infiltration up-regulated by OVA in lung tissue. We focused on decrease of cell infiltration by PN. Intercellular adhesion molecule-1 (ICAM-1) and L-selectin regulate IgE production by controlling mast cell accumulation at sites of inflammation. And then we investigated the mRNA and protein levels of ICAM-1 and L-selectin in bone marrow mast cells (BMMC). BMMC were incubated with 10 ng/ml of TNF-alpha fnand IL-3 plus 1, 10 and 100 £gg/ml of PN for 4 hours. The mRNA and protein level were measeured by using RT-PCR and Fluorescence activated cell sorter (FACS). PN had down-regulated both mRNA and protein of ICAM-1, however, no difference at mRNA and protein of L-selectin in BMMC. Together all things, PN has anti allergy effects on asthma, based on down-regulation of ICAM-1.
Acknowledgements: This study was supported by a grant from Seoul R&BD Program, Republic of Korea.
Various fungi isolated from asthmatic children’s homes induce asthma like allergic lung disease in mice. (36.2)
Authors: Porter Paul C , Corry David , Delclos George L , Vaidya Swapnil , Kheradmand Farrah 
Published: January 2023

Abstract
Fungal exposure has been associated to allergic lung diseases (including asthma) for over a century. The current asthma model holds that fungal exposure acts merely as antigens triggering long developed pre-existing sensitivity. We challenge this assumption and demonstrate A. niger inhalation can lead to the development of asthma-like allergic lung disease at high doses and at lower doses could act as a Th2 adjuvant allowing develop of allergic responses to a secondary benign antigen. Demonstrating that one fungi could illicit a profound allergic response, we wanted to investigate the allergic lung responses of other fungi. 13 fungi were isolated from the homes of asthmatic children and used to intra-nasally challenge normal C57Bl/6 mice. Select fungi were chosen for dose-dependent analysis and fungal clearance. All fungi analyzed induced at least minor allergic lung disease however the levels varied widely. Fungal clearance appeared to decrease with an increase in conidia size. Our results suggest that the general response to fungal conidia inhalation is the development of allergic lung responses.
Dissecting the role of Tyk2 in IL-12 signaling (38.11)
Authors: Maxwell Sarah Sollid , Mozaffarian Afsaneh , Kugler David , Arnett Heather , Gabel Christopher 
Published: January 2023

Abstract
Tyrosine kinase 2 (Tyk2), a member of the Jak family of non-receptor associated kinases, has been implicated in transducing signals mediated by IL-12, IL-23 and IFNα. A strain of mice (B10.Q/J) bears a missense mutation in the pseudokinase domain of Tyk2 which renders the kinase nonfunctional. These mice were initially identified by their heightened resistance to collagen-induced arthritis (CIA) and impaired response to IL-12 and type I IFNs. Following in-house confirmation of disease resistance to CIA, B10.Q/J and wild-type (WT) mice were injected with PBS, IL-12, IL-18, or IL-12+IL-18. Sera were collected at 2 and 24 hours post-injection, and levels of various polypeptide mediators were determined by multi-analyte profiling and ELISA. Compared to WT mice, the absence of functional Tyk2 in the B10.Q/J mice lead to a decrease in circulating IFNγ following IL-12+IL-18 administration. Confirmation that IFNγ output was dependent on Jak involvement was established using the Jak antagonist CP-690,550. This inhibitor was orally administered to WT mice prior to injection of IL-12+IL-18. Sera and tissues collected 2 hours following cytokine injection demonstrated reduced levels of IFNγ and phosphorylated-STAT4. Our results suggest that antagonism of Tyk2 may provide therapeutic benefit in those diseases in which disregulation of cytokines contributes to disease development.
The impact of defective gp130/SOCS3 signaling on the astrocyte response to hyper-IL6 (38.17)
Authors: Frausto Ricardo F , Denyer Gareth , Scheller Jurgen , Rose-John Stefan , Jenkins Brendan J , Ernst Matthias , Campbell Iain L 
Published: January 2023

Abstract
Astrocytes derived from Y757F mutant mice defective in gp130-SHP2/SOCS3 signaling were investigated into their ability to respond to IL-6. Compared with WT astrocytes, Y757F astrocytes treated with hyper-IL6, had higher and more sustained activation of STAT3, while the levels of pY-SHP2 and pERK remained unchanged. Gene expression was investigated by Affymetrix gene chip analysis. At 2 hr, 306 genes were upregulated in WT astrocytes and of these, 28 did not increase in Y757F astrocytes. Of 238 genes upregulated in Y757F astrocytes, 9 were not upregulated in WT astrocytes. Some 99 genes were downregulated in WT astrocytes and of those 55 were not decreased in Y757F astrocytes. In WT astrocytes after 12 hrs the level of expression of many genes was reduced back to or near levels seen in the untreated cells, however, in Y757F astrocytes 109 genes either maintained their 2hr upregulated levels or were further increased. A number of candidate genes upregulated by hyper-IL6 in WT and Y757F astrocytes were not upregulated in astrocytes lacking STAT1. In conclusion, hyper-IL6 stimulated gp-130 SHP2/SOCS3 signaling in astrocytes not only moderates the gp-130-STAT pathway but also directly regulates the transcriptional activity of a number of genes many of which are STAT1-dependent. Support: NSW Spinal Cord Injury and Other Neurological Conditions Project Grant.
IL-15 Receptor alpha increases the stability and promotes secretion and bioactivity of the short signal peptide variant of IL-15 (38.3)
Authors: Bergamaschi Cristina , Jalah Rashmi , Kulkarni Viraj , Rosati Margherita , Valentin Antonio , Zhang Gen-mu , Alicea Candido , Zolotukhin Andrei S. , Felber Barbara K. , Pavlakis George N. 
Published: January 2023

Abstract
Two isoforms of interleukin-15 (IL-15) are known, containing a long signal peptide (LSP) or a short signal peptide (SSP), respectively. The two forms are produced by alternatively spliced mRNAs. It has been proposed that SSP IL-15 remains exclusively intracellular and its function is not known. We show that, similar to LSP IL-15, SSP IL-15 is stabilized and secreted efficiently upon coexpression of IL-15 Receptor alpha (IL-15Ra). Co-injection of mice with SSP IL-15 and IL-15Ra expressing plasmids showed increased plasma levels of bioactive IL-15 and mobilization and expansion of NK and T cells. Therefore, SSP IL-15 is secreted and bioactive when produced as a heterodimer with IL-15Ra in the same cell, though its apparent stability is lower compared to LSP IL-15, due to different intracellular processing. When both LSP IL-15 and SSP IL-15 are produced in the same cell they compete for the binding to IL-15Ra, and result in lower levels of bioactive IL-15. Therefore, co-expressed SSP IL-15 acts as competitive inhibitor of LSP IL-15. This suggests that usage of alternative splicing is an additional level of control of IL-15 activity. Expression of both SSP and LSP forms of IL-15 appears to be conserved in many mammals, suggesting that SSP may be important for expressing a form of IL-15 with lower magnitude and duration of biological effects.
These results support and expand our conclusions (Bergamaschi, J Biol Chem. 2008; 283:4189) that IL-15Ra needs to be co-expressed in the same cell with IL-15 for biological activity, and that IL-15Ra should be considered a part of the heterodimeric IL-15 cytokine, rather than part of the receptor.
Investigating the functional biology of IL-25 during helminth infection (38.6)
Authors: Saenz Steven A , Zaph Colby , Mohrs Markus , Budelsky Alison , Artis David 
Published: January 2023

Abstract
Recent studies have demonstrated key functions of interleukin (IL) -25 in TH2 cytokine-mediated host protective immunity and exacerbation of allergic airway inflammation, however the cell lineages targeted by IL-25 to elicit such responses remains unclear. We show that IL-25 acts through an innate cell mechanism to drive TH2 cytokine responses. Utilizing IL-4/eGFP reporter mice that express green fluorescent protein (GFP) under the IL-4 loci, we demonstrated that IL-25 specifically induced a c-kit+ cell population in the mesenteric lymph nodes. This population was also present in the Peyer's patches, cecal patch, and peritoneum of treated mice. Despite displaying a cell morphology similar to classical mast cells, the IL-25-induced c-kit+ cell population lacked expression of FcεR1 and surface bound IgE. Additionally, IL-25 elicited a TH2 cytokine response and induced this c-kit+ cell population independently of IL-3 and SCF signaling, pathways known to regulate mast cell development. Furthermore, we demonstrated that in mice deficient in the receptor for IL-25 or IL-17A, IL-17Rb and IL-17Ra respectively, the IL-25-mediated induction of this c-kit+ population was lost. Thus, these data suggest that IL-25 acts through a mast-cell independent mechanism to promote TH2 cytokine responses, which is dependent on both IL-17Ra and IL-17Rb.