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Deficient of IL-18 in mice leads to the reduction of neuropeptides in the amygdala related with behavioral change

ABSTRACT: Interleukin (IL)-18 is recognized as a multifunctional mediator in inflammation and immune responses. In addition, the production of IL-18 is stimulated by physiological and/or psychological stress implicated in several behavioral disorders. However, it still remains unclear about the role of IL-18 on the central nervous system. In this study, we analyzed gene expression of 6 brain regions; the olfactory bulb, prefrontal cortex, striatum, amygdala, hypothalamus, and hippocampus. Microarray analysis indicated the regional differences of expression in IL-18-/- mice. In particular, the most profound change was observed in the amygdala, in which 1,237 genes were differentially expressed.

ORGANISM(S): Mus musculus

PROVIDER: GSE19522 | GEO | 2010/12/01

SECONDARY ACCESSION(S): PRJNA122233

REPOSITORIES: GEO

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Deficient of IL-18 in mice leads to the reduction of neuropeptides in the amygdala related with behavioral change

Project description:Interleukin (IL)-18 is recognized as a multifunctional mediator in inflammation and immune responses. In addition, the production of IL-18 is stimulated by physiological and/or psychological stress implicated in several behavioral disorders. However, it still remains unclear about the role of IL-18 on the central nervous system. In this study, we analyzed gene expression of 6 brain regions; the olfactory bulb, prefrontal cortex, striatum, amygdala, hypothalamus, and hippocampus. Microarray analysis indicated the regional differences of expression in IL-18-/- mice. In particular, the most profound change was observed in the amygdala, in which 1,237 genes were differentially expressed. We purchased IL-18-/- mice and C57BL/6 mice from Charles River Japan . To produce F1 generation mice, three male IL-18-/- mice were mated with six female C57BL/6J mice. We mated F1 mice and created their F2 littermates. Six week-old F2 mice littermates were weaned. At 12 weeks, mice were sacrificed at 14:00 under general anesthesia with diethyl ether. After the systemic perfusion with cold phosphate-buffered saline through the heart using a syringe attached to a 21-G needle, the whole mouse brains were removed. Coronal brain sections (1 mm thick) were prepared on ice using a brain slicer . The olfactory bulb was sliced between 3.5 and 4.5 anterior to bregma. The prefrontal cortex was sliced between 2.5 and 3.5 mm anterior to bregma. The striatum was sliced between -0.5 and 0.5 mm posterior to bregma. The hypothalamus, the amygdala, and the hippocampus were sliced between 1.5 and 2.5 mm posterior to bregma. Total RNA was immediately prepared from these samples using TRIzol and purified by RNeasy kit.

2010-12-01 | E-GEOD-19522 | biostudies-arrayexpress

Transcription profiling by array of mouse amygdala to detect transcripts regulated by psychological stress

Project description:Detection of transcripts regulated by psychological stress in mouse amygdala. Prior to experiments mice were kept undisturbed for one week in their home cages. Restraint stress was performed during the light period of the circadian cycle. Control animals were left undisturbed and stressed animals were subjected to a six hour restraint stress session in a separate room. The mice were placed in their home cages in wire mesh restrainers secured at the head and tail ends with clips

2013-04-01 | E-MTAB-1519 | biostudies-arrayexpress

Treatment of TRAMP-C2-Ras tumors with IL-27 and IL-18 therapies

Project description:Interleukin-27 (IL-27) can partially reduce tumor growth in several animal models, including pros-tate cancer. We describe our findings on the effects of IL-27 gene delivery on prostate cancer cells and how sequential therapy with IL-18 enhances the efficacy of IL-27. We applied IL-27 and IL-18 deliv-ery with the goal of reducing prostate tumor growth, first in cell culture and then in an immunocom-petent mouse model. The combination of IL-27 followed by IL-18 (2718) successfully reduced can-cer cell viability, with significant effects found for a particular combination sequence. Interestingly, when we compared the 2718 combination with a single cytokine targeted to IL-6R via an oligo-peptide (27pepL) recently developed by our group, we observed similar efficacy. This efficacy was further enhanced when 27pepL was sequenced with IL-18 (27pepL18)

2021-07-27 | GSE178142 | GEO

IL-18 mediates sickle cell cardiomyopathy and inducible ventricular arrhythmias

Project description:Rationale. Sickle cell cardiomyopathy is characterized by prolonged QTc, myocardial fibrosis, diastolic dysfunction, and vulnerability to ventricular tachycardia (VT). Based on previous reports, IL-18 mediates cardiac fibrosis and its promoter SNPs are associated with sudden cardiac death in a non-sickle population. We, therefore, hypothesized that IL-18 may mediate cardiomyopathy and VT in sickle cell disease. Findings. Sickle cell patients with evidence of myocardial fibrosis demonstrated greater IL18 expression. Patients with higher IL18 gene expression levels also exhibited increased QTc intervals and overall mortality. A novel SNP within IL-18, rs5744285, was associated with both QTc and IL-18 expression levels. Similar to sickle cell patients, sickle mice demonstrated increased cardiac fibrosis and prolonged action potential duration (APD) associated with higher VT inducibility. Administration of exogenous IL-18 acutely ex vivo to hearts resulted in increased triggered activity and VTs while inhibition of IL-18 resulted in reduced cardiac NFkB expression, fibrosis, and dysfunction in sickle mice. Conclusions. IL-18 is associated with prolonged QTc, myocardial fibrosis, and mortality in sickle cell patients, and prolonged APD associated with heightened VT susceptibility in sickle mice. Inhibition of IL-18 improves cardiac function, in part, via NFκB. Inflammatory cytokines contribute to the development of sickle cardiomyopathy and inducible VT.

2018-10-31 | GSE89373 | GEO

IL-18 nAbs block deleterious inflammatory cytokines induced by acute β-AR stimulation in heart

Project description:To directly test whether inhibition of IL-18 by IL-18 neutralizing monoclonal antibodies (IL-18 nAbs) is sufficient for blocking the inflammatory responses of heart caused by acute β-adrenergic insult, mice were subjected to intraperitoneal injection with rat IL-18 nAbs or IgG as a negative control 1hr after isoproterenol treatment.

2016-05-31 | GSE82034 | GEO

Gene expression profiling of IL-18 stimulated, in vitro differentiated mouse mucosal mast cells (MMC)

Project description:The aim of the present study was to clarify the role of IL-18 in mouse mast cell functions. Mouse mucosal mast cells (Balb/c) were differentiated in the presence of IL-3 (5 ng/ml), SCF (40 ng/ml), IL-9 (10 ng/ml) and human TGFbetaI (2 ng/ml) for >4 weeks. Cells were then stimulated by 100 ng/ml IL-18 for 2 hours to monitor the direct effect of IL-18. Treated samples were compared to the untreated ones in a paired experimental setting. Keywords: expression microarray, mast cell, IL-18

2008-09-26 | GSE9736 | GEO

IL-18BP is a secreted immune checkpoint and barrier to effective IL-18 immunotherapy

Project description:Recombinant cytokines were the first modern immunotherapies to produce durable cures in metastatic cancer, but their application has been hampered by only modest efficacy and limited tolerability. Next-generation cytokine therapies are therefore under development to overcome the biological limitations of native cytokines. By analyzing single-cell transcriptomic data from tumor infiltrating lymphocytes (TIL), we found that components of the Interleukin-18 (IL-18) pathway are upregulated on activated and dysfunctional TIL, suggesting that IL-18 therapy could potentially restore anti-tumor immunity by stimulating these key effector cells. However, recombinant IL-18 therapy has consistently failed to demonstrate anti-tumor efficacy in clinical trials. Here we show that the secreted, high-affinity decoy receptor IL-18BP is frequently upregulated in the tumor microenvironment of diverse human cancers and syngeneic murine tumor models. Using directed evolution, we engineered a ‘decoy-resistant’ IL-18 (DR-18), which maintains signaling potential, but is impervious to binding and inhibition by IL-18BP. In contrast to wild-type IL-18, DR-18 exhibits potent anti-tumor efficacy as monotherapy and in combination with anti-PD-1 checkpoint immunotherapy in multiple tumor models. Mechanistically, DR-18 drives the development of poly-functional effector CD8+ T cells, decreases the prevalence of exhausted CD8+ T cells expressing the transcription factor TOX, and expands the pool of TCF1+ precursor CD8+ T cells. DR-18 also enhances NK cell activity and maturation to effectively treat anti-PD-1 resistant tumors that have lost MHC class I surface expression. Together, these results highlight the IL-18 pathway as a powerful target for immunotherapeutic intervention and implicate the secreted immune checkpoint IL-18BP as an obstacle to effective IL-18 immunotherapy.

2020-06-29 | GSE146609 | GEO

RNA squencing of human NK cells activated with IL-15, a combination of IL-12, IL-15, and IL-18, or with a trimeric fusion protein 18/12/TxM

Project description:Gene expression analysis of human NK cells at baseline, Day 1, and Day 6 after activation with IL-15, IL-12/15/18, or the 18/12/TxM molecule

2022-02-02 | GSE166268 | GEO

Cross-Species Single-cell Comparative Analysis of Amygdala

Project description:The amygdala or amygdala-like structure in the brain are found in all vertebrates, and plays a critical role for emotional processing. But the cellular architecture of amygdala and how they evolved are still elusive. Here, we generated single-nucleus RNA-sequencing data for more than 200,000 cells in human, macaque, mouse and chicken amygdala. Abundant neuronal cell types derived from different subnuclei of amygdala were identified in all datasets. Cross-species analyses revealed GABAergic neurons and GABAergic neuron-enriched subnuclei of amygdala were well-conserved in cellular composition and marker gene expression, whereas glutamatergic neuron-enriched subnuclei were relatively divergent. Furthermore, we discovered that LAMP5+ interneurons were much more numerous in primates, while DRD2+ GABAergic neurons, LAMP5+ and SATB2+ glutamatergic neurons were predominant in the human central amygdalar nucleus (CEA) and basolateral amygdala complex (BLA), respectively. In addition, we also identified GABAergic neuron-enriched subnuclei of amygdala in the chicken. Altogether, our study highlight extremely cell-type diversity in the amygdala across species and their species-specifc adaptations.

2022-12-13 | GSE195445 | GEO

Regulatory NK cells: IL-18-elicited NK cells with immunosuppressive functions

Project description:Cancer-induced tolerance mostly involves myeloid suppressor cells, regulatory T cells and immunosuppressive cytokines, which all subvert adaptive immune responses against tumor cells. Here, we show that a subset of innate effectors, c-kit expressing NK cells (Kit+ NK), can participate in tumor-induced tolerance by compromising the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells can convert Kit- into Kit+ NK cells that overexpress B7-H1/PD-L1 molecules. Upon tumor inoculation, Kit+ NK cells rapidly develop in lymphoid organs in a IL-18R/MyD88 dependent manner and directly kill Kit- NK cells in a B7-H1/PD-1-dependent manner, thereby promoting the progression of NK-controlled cancers. Our data suggest that, in a tumoral context, IL-18 subverts antitumor NK cell functions. Systemic neutralization of IL-18 by IL-18-binding protein may improve the NK-mediated immunosurveillance. Keywords: cell type comparison

2009-03-01 | GSE9431 | GEO

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