bluuebunny/crossref_metadata_2025_split huggingface dataset:
ICOS regulates CD4 T cell exit from the lymph nodes (95.15)
Authors: Moore Tamson V. , Clay Bryan S. , Histed Alex , Shilling Rebecca A. , Sperling Anne I. 
Published: January 2023

Abstract
Inducible costimulator (ICOS) belongs to the CD28 family of costimulatory receptors. Although ICOS has been found to augment CD4 T cell differentiation and cytokine production, its effects on proliferation and survival are controversial. To dissect the effects of ICOS on T cell survival and proliferation, ICOS-/- or wild-type TCR-transgenic T cells were adoptively transferred and followed after immunization. ICOS-/- cells divided significantly less than wild-type CD4 T cells by CFSE dilution. Unexpectedly, when the total number of cells was examined, more ICOS-/- cells were found in the lymph nodes and fewer in the spleen. We then shifted our focus to the effects of ICOS on CCR7 and CD62L, receptors known to retain cells in the lymph nodes. Interestingly, ICOS-/- TCR-transgenic cells had a defect in down-regulation of CD62L and CCR7 compared to wild-type cells. In a model of Th2-mediated airway inflammation, ICOS-/- mice had significantly fewer CD4 T cells in their airways than wild-type mice, and the CD4 T cells in the draining lymph node expressed higher levels of CCR7. Finally, ICOS-/- cells migrated more to the draining lymph nodes than the spleen compared to wild-type cells in inflamed mice. Together, these data suggest that ICOS-/- CD4 T cells have defective down-regulation of CCR7 and CD62L, leading to a defect in cell egress from lymph nodes and migration to sites of inflammation.
Targeting regulatory T cells in vaccination: In silico identified small molecule CCR4 antagonists exert adjuvant activity (96.12)
Authors: BAYRY Jagadeesh , Tchilian Elma Z , Davies Matthew N , Beverley Peter C.L. , Flower Darren R , Tough David F 
Published: January 2023

Abstract
The efficacy of vaccines can be greatly improved by the addition of adjuvants, which enhance and modify immune responses. At present, few adjuvants are available for human use, and the most common, alum, stimulates immunity that is suboptimal for protection against many infections. We have used computer modeling and virtual screening to identify potential small molecule adjuvants that target specific cell receptors. The chemokine receptor CCR4 was posited as an adjuvant target, based on its expression on CD4+CD25+ regulatory T cells, which normally act to down-regulate immune responses. A high proportion (16%) of small molecules that were predicted by virtual screening to be CCR4 antagonists were able to inhibit CCR4-mediated cellular migration in vitro. Importantly, CCR4 antagonists enhanced human T cell proliferation in an in vitro immune response model and increased T cell and antibody responses in vivo when used in combination with vaccines. The results suggest that in silico screening will prove an aid to the rational design of molecular vaccine adjuvants targetting specific receptors.
Inhibition of VEGF reduces antigen specific CD8 T cell mediated CNS vascular permeability (96.16)
Authors: Johnson Aaron J. , Suidan Georgette L. , Chen Yi , Pirko Istvan 
Published: January 2023

Abstract
CD8 T cells and vascular endothelial growth factor (VEGF) have been implicated in promoting vascular permeability in neurological disease. We have created an in vivo system to study BBB disruption using the Theilers murine encephalomyelitus virus (TMEV) model of multiple sclerosis. During acute TMEV infection, 70% of CNS infiltrating CD8 T cells are specific for a TMEV peptide, VP2 121-130, presented in the context of the Db Class I molecule. Intravenous injection of the VP2 121-130 peptide during the peak of CD8 T cell expansion in the CNS results in fatal vascular permeability characterized by: 1.) Astrocyte activation as detected by GFAP expression, 2.) Alteration of blood brain barrier tight junction proteins ZO-2, Occludin and Claudin 5, 3.) Gadolinium enhancing lesions on MRI, and 4.) Severe motor deficit. Prior to these overt changes in CNS vascular permeability we observe dramatic increases in neuronal VEGF expression. Inhibition of VEGF results in a titratable reduction of CNS vascular permeability, demonstrating the importance of this cytokine in BBB disruption. Inhibition of VEGF also resulted in greatly reduced phosphorylation of CNS VEGF receptor Flk-1, demonstrating the appropriate blockade of VEGF was occurring in the CNS. These experiments demonstrate the therapeutic potential of VEGF inhibition in neurologic diseases characterized by CNS vascular permeability.
Production of a cytokine inducing IL-2 production from T cell by dendiritic cells stimulated with a sesquiterpene compound TG651 (96.19)
Authors: Kang Hyun-Jung , Im Sun-A , Lee Young-Hee , Lee Young-Ran , Song Sukgil , Lee Chong-Kil 
Published: January 2023

Abstract
Dendritic cells (DCs) have been known to produce cytokines such as IL-1, IL-6, IL-10, IL-12, IFN-á and IFN-ã. None of those cytokines has been shown to activate T cells to produce IL-2 by itself. Here, we report that DCs stimulated with TG651, a sesquiterpene compound, produce a cytokine that induces IL-2 production from T cells. The cytokine, termed as IL-2SF, was produced from DCs as a membrane bound form as well as a soluble form. IL-2SF was produced from DCs within 5 min after TG651 stimulation, and did not require new protein synthesis, although presence of approximately 10 % fetal bovine serum was required for optimal production. IL-2SF activated both CD4 and CD8 T cells to produce IL-2. Soluble form of IL-2SF appeared to be stable at neutral - acidic condition, but destroyed readily at alkaline condition when treated at 56oC for 30 min. Ultrafiltration experiments showed that the MW of soluble form of IL-2SF is larger than 50 KD. Although the molecular entity of IL-2SF remains to be elucidated, the present study may lead to discover a novel cytokine that induces IL-2 production from T cells.
The crucial role for the first gata-1 site in the exon1 of CCR3 in its transcription. (96.20)
Authors: Uhm Tae Gi , Kim Byung Soo , Kang Jin Hyun , Park Choon-Sik , Chung Il Yup 
Published: January 2023

Abstract
GATA-1 is shown to regulate development/differentiation of myeloid lineages including eosinophils. CCR3 is almost exclusively expressed on eosinophils and has been extensively studied for a molecular target to interfere eosinophils-associated diseases such as asthma. There are several putative gata-1 sites in exon1 of CCR3 and the regions flanking the exon1. To know whether GATA-1 is involved in CCR3 expression and further which gata-1 site is responsible for GATA-1 binding, we performed chromatin immunoprecipitation assay and mutation analysis using peripheral blood eosinophils, developing eosinophils, and cell lines that express varying degrees of CCR3 and GATA-1. We found that GATA-1 strongly bound to the regions in the exon1 and the intron1 downstream the exon1. K562 cells, which endogenously express the highest level of GATA-1, exhibit much higher CCR3 reporter activity than cells expressing low or intermediate levels of GATA-1. Introduction of DN-GATA-1 resulted in a decrease in CCR3 reporter activity. Among eight point mutants for the gata-1 sites, the first gata-1 sequence of exon1 is solely responsible for CCR3 transcription, which was subsequently confirmed by EMSA.
CD8 T CELLS PRODUCING IFN-G AND IL-17 INDUCE THE INNATE IMMUNE RESPONSE REQUIRED FOR T CELL MEDIATED RESPONSES IN THE SKIN (96.3)
Authors: Kish Danielle D. 
Published: January 2023

Abstract
Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to skin sensitization and challenge with hapten. Hapten-primed CD8 T cell recruitment into the challenged skin to mediate CHS requires prior CXCL1/KC and CXCL2/MIP-2 directed neutrophil infiltration. Factors inducing KC and MIP-2 production in the skin challenge site during CHS to dinitrofluorobenzene (DNFB) were investigated. KC and MIP-2 were produced 3-6 h after challenge of DNFB sensitized, but not unsensitized, mice and required hapten-specific CD8 T cells. Hapten-primed CD8 T cells stimulated hapten-labeled endothelial cell (EC) cultures to produce KC that was blocked by either anti-IFN-g or anti-IL-17 mAb. Addition of rIFN-g plus rIL-17 stimulated cultured EC to produce KC. DNFB sensitization induced hapten-specific CD8 T cell populations producing IFN-g; and IL-17. Induction of KC and MIP-2 in the skin challenge site of sensitized wild type mice was accompanied by expression of IFN-g, IL-17, and IL-21 mRNA and all were absent following challenge of sensitized IFN-g-/- and IL-17-/- mice. Co-transfer of CD8 T cells from sensitized IFN-g-/- and IL-17-/- mice, but not each population alone, to naïve mice restored hapten challenge induced KC production. Activation of hapten-primed CD8 T cell populations producing IFN-g and IL-17 is required to induce production of the KC and MIP-2 required to initiate elicitation of CHS.
Fibrotic footprint of Oncostatin M-induced pulmonary disease (97.10)
Authors: Mozaffarian Afsaneh , Anders Penny M , Trueblood Esther S , Luzina Irina G , Todd Nevins W , Atamas Sergei P , Arnett Heather A 
Published: January 2023

Abstract
Oncostatin M (OSM), an IL-6 family cytokine, has been implicated in a number of biological processes including the induction of inflammation and modulation of extracellular matrix (ECM). Recently, we observed that OSM is elevated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis as well as scleroderma. In mice, delivery of OSM to the lungs results in recruitment of inflammatory cells and an increase in collagen deposition in the lungs, with pathological correlates to characteristic human interstitial lung disease. We used genetically modified mice to show that the fibrotic response is largely independent of B and T lymphocytes, eosinophils and mast cells. To investigate the relationship between OSM-induced inflammation and OSM-induced fibrosis, we used both protein and genomic array approaches to generate a "fibrotic footprint" for OSM. While the IL-4/IL-13 and TGF-β pathways are generally intertwined in fibrosis, we show that OSM is capable of driving lung fibrosis independent of these pathways. For comparison, we show the expression patterns of OSM versus bleomycin-induced lung fibrosis to highlight the unique mechanisms underlying disease pathogenesis. The demonstration that OSM is a potent mediator of lung inflammation and ECM accumulation, and upregulated in patients, provides a rationale for targeting OSM in human disease.
IL-6 modulates TGF-β expression in skin from IL-6 deficient mice (97.11)
Authors: Luckett-Chastain Lerin R , Smith Mackenzie L , Gallucci Randle M 
Published: January 2023

Abstract
IL-6 and Tgf-β have been shown to play a role in skin development and maintenance. However, a link between these two cytokines has yet to be identified therefore; therefore, in this study we investigated the modulation of Tgf-β1 and Tgf-βR2 by IL-6 in skin. Recombinant IL-6 treatment of IL-6KO lattices and intradermal injections of IL-6 into unwounded mice showed a significant induction of Tgf-β1 mRNA and protein, where Tgf-β1 expression localized in the dermis, while Tgf-βR2 expression resided primarily in the epidermis in IL-6KO mice. IL-6 also increased Tgf-βR2 mRNA and protein expression, and potentiates TGFb mediated decreases in proliferation in cultured keratinocytes. Wounded IL-6KO and C57BL/6 control mice showed Tgf-β1 and βR2 mRNA expression was significantly greater in unwounded and seven day-old wounds from WT mice, however; protein expression was not different. Use of inhibitors indicated that IL-6 modulates Tgf-β through a Mapk/Erk dependent mechanism. These studies indicate that IL-6 has the ability to modulate the expression of Tgf-β and Tgf-βR2 mRNA in dermal fibroblasts and unwounded skin through a Mapk/Erk dependent mechanism. Protein expression levels indicated additional regulation by factors other than IL-6 within the wound. IL-6 treatment also potentiates the differentiative effects of Tgf-β on cultured keratinocytes. These results may provide a possible mechanism defining the role of IL-6 in skin maintenance and may indicate a new association of IL-6 with Tgf-β in pathologies associated fibrosis.
This work was funded by NIH/NIGMS grant R01 GM067745.
An accessory role for B cells in the IL-12 induced activation of resting murine NK lymphocytes (97.2)
Authors: Haddad Evette Adam , Senger Laura , Takei Fumio 
Published: January 2023

Abstract
IL-12 is produced during early innate immune responses. Via their potent production of IFN-γ, NK cells are important mediators of the anti-microbial and anti-cancer effects of IL-12. Since the IL-12 receptor is expressed on activated but not resting NK cells, it is still unclear how IL-12 stimulates resting NK cells. Here we reveal that the activation of resting murine NK cells by IL-12 is dependent upon B cells. Upon stimulation of bulk spleen cells with IL-12, NK cells are the main source of IFN-γ. The activation of NK cells with IL-12 is dependent on endogenous IL-18 as spleen cells from IL-18 knock out (KO) mice are poorly stimulated, and purified NK cells are not stimulated with IL-12 unless IL-18 is also added. To stimulate purified NK cells with IL-12 alone, B cells, but not NKT, macrophages or dendritic cells, are absolutely required. Co-culturing B cells with NK cells induces IFN-γ production by NK cells in a contact-dependent manner. Purified B cells from IL-18 KO mice are not able to stimulate NK cells in the presence of IL-12, but IL-18 KO NK cells are still stimulated with IL-12 as long as normal B cells are present. This suggests that B cells may be a source of endogenous IL-18 during IL-12 stimulation. Intraperitoneal injection of IL-12 induces higher levels of IFN-γ and IL-18 in the sera of wild type mice than those of B cell deficient mice. Thus, we propose that B cells are important accessory cells to NK cell stimulation by IL-12.
(Supported by a grant from the National Cancer Institute of Canada)
Anti-inflammatory effects of cannabinoid receptor-2-selective agonists in immune cells (98.12)
Authors: Adhikary Sabina , Ganea Doina 
Published: January 2023

Abstract
A few studies have been published showing effects of cannabinoids in modulating immune response from T helper cell type 1 (Th1) to T helper cell type 2 (Th2) in a model of Legionella pneumophila infection. Cannabinoids act through two cloned receptors, CB1 and CB2. The CB1 receptor is expressed primarily in the CNS, whereas the CB2 receptor is highly expressed in immune cells in the periphery. Previous results from our laboratories indicated that the CB2 agonist had an anti-inflammatory effect on dendritic cells (DCs) and T cells. DCs differentiated in the presence of CB2 agonist produced less IL-12 upon LPS stimulation and T cells produced less IFN-gamma when co-cultured with these DCs in syngeneic culture in the presence of specific antigen. Here, we report that CB2 agonist treatment of DCs resulted in reduced STAT-1 phosphorylation. Also, treatment of polyclonally activated CD4+ T cells resulted in reduced expression of IL-12 receptor beta 2 chain, which correlated with decreased IFN-gamma production. Our data lead us to believe that CB2 agonists can modulate immune responses by acting directly on CD4+ T cells or through their effects on DCs.
This work is supported by NIH/NIAID R01AI05230, and training grant T32 DA07237 (SA)
Macrophage migration inhibitory factor upregulates expression of receptor activator of NF-kappa B ligand(RANKL) in rheumatoid arthritis synovial fibroblasts (98.16)
Authors: Lee Sang Heon , Kim Kyoung Woon , Kim Hae Rim , Cho Mi La , Min Jun Ki , Seo Youngil , Jung Young-Ok , Lee Chang-Keun 
Published: January 2023

Abstract
Rheumatoid arthritis(RA) is characterized by chronic progressive inflammatory destruction of bone and cartilage, which is mediated by inflammatory cytokines. Macrophage migration inhibitory factor (MIF) is abundantly expressed in the sera, synovial fluids and synovial tissues of RA patients, and its level correlates with disease activity. The aim of this study is to explore the role of MIF in regulating RANKL expression and osteoclastogenic activity in RA synovial fibroblasts (FLS). FLS were separated from the synovium of RA patients and stimulated with rMIF. RANKL expression was determined by real time PCR, western blot and immunostaining. Osteoclast precursor cells were cocultured with MIF-stimulated RA FLS and subsequently stained for tartrate-resistant acid phosphatase (TRAP) activity. MIF upregulated the expression of RANKL in RA-FLS. The increased expression of RANKL mRNA and protein was completely blocked by AP-1 inhibitor (curcurmin), p38 MAPK inhibitor (SB203580) or JAK II-STAT2(AG490). Increased number of TRAP positive cells were observed when osteoclast precursor cells were incubated with MIF-pretreated RA FLS. These results suggest that MIF could be involved in the inflammatory bone destruction by regulating RANKL expression in RA FLS. The interaction between MIF and RANKL could be a potential gateway leading to new therapeutic approach in treating bone destruction in RA.
Regulation and function of newly-recognized IL-1 family cytokines in human bronchial epithelial cells (98.18)
Authors: Kato Atsushi , Chustz Regina T , Schleimer Robert P 
Published: January 2023

Abstract
The IL-1 family of cytokines, which now includes 11 members, is well known to participate in inflammation. Although the latest IL-1 family cytokines (IL1F5-11) have been shown to be expressed in airway epithelial cells, the regulation of their expression has not been studied. We investigated the regulation of IL1F5-11 in normal human bronchial epithelial cells. Messenger RNAs for IL1F6 and IL1F9, but not IL1F5 or IL1F10, were significantly up-regulated by TNF, IL-1b, IL-17 and TLR3 ligand dsRNA. Messenger RNAs for IL1F7, IL1F8 and IL1F11 (IL-33) were weakly up-regulated by some of the cytokines tested. Notably, mRNAs for IL1F6 and IL1F9 were synergistically enhanced by the combination of TNF/IL-17 or dsRNA/IL-17. IL1F9 protein was detected in the supernatant following stimulation with dsRNA (1.6 ng/ml) or a combination of dsRNA and IL-17 (2.5 ng/ml). IL1F6 protein was detected by western blot. We screened the receptors for IL1F6 and IL1F9 and found that fibroblasts expressed these receptors. We found that IL1F9 activated the MAPKs and the transcription factors including NFkB in primary normal human lung fibroblasts. IL1F9 also stimulated the induction of CXCL8 and CCL20. These results suggest that epithelial activation by respiratory viral infection and exposure to cytokines from Th17 cells (IL-17) may amplify neutrophilic inflammation in the airway via induction of IL1F6 and IL1F9.
The protective effect of Vitamin C on cardiomyocytes damage and heart failure (98.22)
Authors: kim hyemin , Kang Jae Seung , Maeng Hyung Gun , Bae Se Yeon , Lee Na Eun , Kong Joo Myoung , Hwang Young Il , Lee Wang Jae 
Published: January 2023

Abstract
In the heart, reactive oxygen species play a pivotal role in the apoptosis of cardiomyocytes, which is one of the major factors for heart failure. Although there are several reports regarding the effect of vitamin C as an antioxidant scavenging free radicals on patients with cardiovascular disease, the specific mechanism is still being elucidated. In this study, the effects of vitamin C on the prevention and protection of heart failure are investigated under stressful conditions composed by cold water and restraint using Gulo(-/-) mice which could not synthesize vitamin C endogenously. Survival rates of mice checked under stressful conditions showed that Gulo(-/-) mice were more susceptible to stress than wild type or vitamin C-supplemented Gulo(-/-) mice. The levels of heart failure-related proinflammatory cytokines were examined, where the levels of TNF-alpha, IL-1 alpha, and IL-6 were increased in Gulo(-/-) mice without stress. In Gulo(-/-) mice under stressful conditions, not only the levels of IL-1 alpha, TNF-alpha and soluble Fas ligand but also lipid peroxidation were remarkably elevated. And, the extensive apoptosis of cardiomyocytes in cardiac tissues from dead Gulo(-/-) mice by stress was observed. Taken together, it is suggested that vitamin C could effectively prevent stress-induced heart failure through the regulation of heart failure-related cytokines and the inhibition of apoptosis of cardiomyocytes.
Identification of lipopolysaccharide binding site on High Mobility Group Box 1 Protein (98.23)
Authors: Youn Ju Ho , Shin Jeon-Soo 
Published: January 2023

Abstract
Lipopolysaccharide (LPS), a bacterial endotoxin, triggers deleterious systemic inflammatory responses when released into blood circulation, causing severe sepsis, organ dysfunction and death. LPS binding components in serum play an important role in modifying LPS toxicity by facilitating its interaction with the LPS signaling receptor, which is expressed on LPS-responsive cells. We have previously shown that HMGB1 is able to bind LPS and this binding can increase LPS-induced TNF-α production in human peripheral blood monocytes. In this report, we identified several LPS binding regions within human HMGB1 sequence by pull-down experiments with synthetic biotinylated peptide derived from HMGB1. Using a conventional sequence-based comparison with several other LPS-binding proteins, we identified similar LPS-binding motifs in LPS-binding peptides from HMGB1, but inhibition assay demonstrated that the capacity of these peptides to interfere with LPS-HMGB1 interaction exhibits different characteristics We are now carrying out further experiments to evaluate which amino acid residues contribute to LPS binding and functional differences between different peptide in LPS-binding capacities. Our studies identified a defined region of HMGB1 involved in LPS binding, thereby implicating a physiological role of human HMGB1 as an LPS-binding protein. [This study was supported by a grant from the Korean Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A080694) and Brain Korea 21 project to Medical Science.]
The Effects of Leukocytes on Early Implantation in the Rhesus Monkey (98.24)
Authors: Rozner Ann E , Durning Maureen , Vielhuber Kathleen , Drenzek Jessica , Dambaeva Svetlana , Golos Thaddeus 
Published: January 2023

Abstract
At the time of implantation and throughout pregnancy, the primate uterus contains numerous leukocytes, consisting primarily of natural killer cells and macrophages. The cytokine balance at the maternal fetal interface and the expression of non-classical MHC class I molecules (HLA-G in humans and Mamu-AG in the rhesus monkey) on the trophoblast cells of the growing embryo are thought to be important immune modulators that allow the semi-allogenic embryo to implant and grow. However, study of the maternal fetal interface in human implantation is not feasible. We have established a co-culture system with rhesus monkey embryos to model implantation. Rhesus blastocysts stage embryos, derived by in vitro fertilization, were co-cultured with peripheral blood NK cells and/or monocytes obtained from the oocyte donor. Embryo growth was monitored and culture media were collected to determine cytokine and chorionic gonadotropin secretion. Trophoblast outgrowths from the embryo were noticeable after 6 days of co-culture. Embryos co-cultured with monocytes did not show signs of growth within the two weeks of co-culture, however embryos co-cultured with both monocytes and NK cells grew at similar rates to controls. Based on these results we conclude that the monocyte/NK cell balance and/or interaction is important and that using a rhesus model may lead to increased knowledge of the role of leukocytes during pregnancy.