scholarly journals Interleukin-4 in the Generation of the AERD Phenotype: Implications for Molecular Mechanisms Driving Therapeutic Benefit of Aspirin Desensitization

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
John W. Steinke ◽  
Spencer C. Payne ◽  
Larry Borish
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Cell Types ◽  
Therapeutic Benefit ◽  
Interleukin 4 ◽  
Prostaglandin E ◽  
Aspirin Desensitization ◽  
Over Expression ◽  
Cysteinyl Leukotriene ◽  
Cox 2

Aspirin-exacerbated respiratory disease (AERD) is explained in part by over-expression of 5-lipoxygenase, leukotriene C4 synthase (LTC4S) and the cysteinyl leukotriene (CysLT) receptors (CysLT1 and 2), resulting in constitutive over-production of CysLTs and the hyperresponsiveness to CysLTs that occurs with aspirin ingestion. Increased levels of IL-4 have been found in the sinus mucosa and nasal polyps of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the upregulation of LTC4S by mast cells and the upregulation of CysLT1 and 2 receptors on many immune cell types. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD reflecting diminished expression of cyclooxygenase (COX)-2. IL-4 can inhibit basal and stimulated expression of COX-2 and microsomal PGE synthase 1 leading to decreased capacity for PGE2 secretion. Thus, IL-4 plays an important pathogenic role in generating the phenotype of AERD. This review will examine the evidence supporting this hypothesis and describe a model of how aspirin desensitization provides therapeutic benefit for AERD patients.

scholarly journals Molecular mechanisms governing circulating immune cell heterogeneity across different species revealed by single cell sequencing

2021 ◽  
Author(s):  
Zhibin Li ◽  
chengcheng Sun ◽  
Fei Wang ◽  
Xiran Wang ◽  
Jiacheng Zhu ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cells ◽  
Evolutionary Biology ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Genetic Regulatory Networks ◽  
Peripheral Blood Mononuclear

Background: Immune cells play important roles in mediating immune response and host defense against invading pathogens. However, insights into the molecular mechanisms governing circulating immune cell diversity among multiple species are limited. Methods: In this study, we compared the single-cell transcriptomes of 77 957 immune cells from 12 species using single-cell RNA-sequencing (scRNA-seq). Distinct molecular profiles were characterized for different immune cell types, including T cells, B cells, natural killer cells, monocytes, and dendritic cells. Results: The results revealed the heterogeneity and compositions of circulating immune cells among 12 different species. Additionally, we explored the conserved and divergent cellular cross-talks and genetic regulatory networks among vertebrate immune cells. Notably, the ligand and receptor pair VIM-CD44 was highly conserved among the immune cells. Conclusions: This study is the first to provide a comprehensive analysis of the cross-species single-cell atlas for peripheral blood mononuclear cells (PBMCs). This research should advance our understanding of the cellular taxonomy and fundamental functions of PBMCs, with important implications in evolutionary biology, developmental biology, and immune system disorders

scholarly journals Genetic associations at regulatory phenotypes improve fine-mapping of causal variants for twelve immune-mediated diseases

2020 ◽  
Author(s):  
Kousik Kundu ◽  
Alice L. Mann ◽  
Manuel Tardaguila ◽  
Stephen Watt ◽  
Hannes Ponstingl ◽  
...  
Keyword(s):  
Fine Mapping ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Meta Analysis ◽  
Cell Types ◽  
Genetic Associations ◽  
Sequencing Data ◽  
Immune Mediated ◽  
Causal Genes ◽  
Causal Variants

AbstractThe identification of causal genetic variants for common diseases improves understanding of disease biology. Here we use data from the BLUEPRINT project to identify regulatory quantitative trait loci (QTL) for three primary human immune cell types and use these to fine-map putative causal variants for twelve immune-mediated diseases. We identify 340 unique, non major histocompatibility complex (MHC) disease loci that colocalise with high (>98%) posterior probability with regulatory QTLs, and apply Bayesian frameworks to fine-map associations at each locus. We show that fine-mapping applied to regulatory QTLs yields smaller credible set sizes and higher posterior probabilities for candidate causal variants compared to disease summary statistics. We also describe a systematic under-representation of insertion/deletion (INDEL) polymorphisms in credible sets derived from publicly available disease meta-analysis when compared to QTLs based on genome-sequencing data. Overall, our findings suggest that fine-mapping applied to disease-colocalising regulatory QTLs can enhance the discovery of putative causal disease variants and provide insights into the underlying causal genes and molecular mechanisms.

scholarly journals Secondary analysis of transcriptomes of SARS-CoV-2 infection models to characterize COVID-19

2020 ◽  
Author(s):  
Sudhir Ghandikota ◽  
Mihika Sharma ◽  
Anil G. Jegga
Keyword(s):  
Differentially Expressed Genes ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Immune Cell ◽  
Gene Clusters ◽  
Cell Types ◽  
Host Protein ◽  
Differentially Expressed ◽  
Protein Interaction Data ◽  
Neuropsychiatric Diseases

ABSTRACTKnowledge about the molecular mechanisms driving COVID-19 pathophysiology and outcomes is still limited. To learn more about COVID-19 pathophysiology we performed secondary analyses of transcriptomic data from two in vitro (Calu-3 and Vero E6 cells) and one in vivo (Ad5-hACE2-sensitized mice) models of SARS-CoV-2 infection. We found 1467 conserved differentially expressed host genes (differentially expressed in at least two of the three model system transcriptomes compared) in SARS-CoV-2 infection. To find potential genetic factors associated with COVID-19, we analyzed these conserved differentially expressed genes using known human genotype-phenotype associations. Genome-wide association study enrichment analysis showed evidence of enrichment for GWA loci associated with platelet functions, blood pressure, body mass index, respiratory functions, and neurodegenerative and neuropsychiatric diseases, among others. Since human protein complexes are known to be directly related to viral infection, we combined and analyzed the conserved transcriptomic signature with SARS-CoV-2-host protein-protein interaction data and found more than 150 gene clusters. Of these, 29 clusters (with 5 or more genes in each cluster) had at least one gene encoding protein that interacts with SARS-CoV-2 proteome. These clusters were enriched for different cell types in lung including epithelial, endothelial, and immune cell types suggesting their pathophysiological relevancy to COVID-19. Finally, pathway analysis on the conserved differentially expressed genes and gene clusters showed alterations in several pathways and biological processes that could enable in understanding or hypothesizing molecular signatures inducing pathophysiological changes, risks, or sequelae of COVID-19.

scholarly journals Cysteinyl Leukotriene Receptor-1 Antagonists as Modulators of Innate Immune Cell Function

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
A. J. Theron ◽  
H. C. Steel ◽  
G. R. Tintinger ◽  
C. M. Gravett ◽  
R. Anderson ◽  
...  
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Cell Types ◽  
Innate Immune ◽  
Human Neutrophils ◽  
Cysteinyl Leukotriene ◽  
Anti Inflammatory ◽  
Cysteinyl Leukotriene Receptor ◽  
Underlying Mechanisms

Cysteinyl leukotrienes (cysLTs) are produced predominantly by cells of the innate immune system, especially basophils, eosinophils, mast cells, and monocytes/macrophages. Notwithstanding potent bronchoconstrictor activity, cysLTs are also proinflammatory consequent to their autocrine and paracrine interactions with G-protein-coupled receptors expressed not only on the aforementioned cell types, but also on Th2 lymphocytes, as well as structural cells, and to a lesser extent neutrophils and CD8+cells. Recognition of the involvement of cysLTs in the immunopathogenesis of various types of acute and chronic inflammatory disorders, especially bronchial asthma, prompted the development of selective cysLT receptor-1 (cysLTR1) antagonists, specifically montelukast, pranlukast, and zafirlukast. More recently these agents have also been reported to possess secondary anti-inflammatory activities, distinct from cysLTR1 antagonism, which appear to be particularly effective in targeting neutrophils and monocytes/macrophages. Underlying mechanisms include interference with cyclic nucleotide phosphodiesterases, 5′-lipoxygenase, and the proinflammatory transcription factor, nuclear factor kappa B. These and other secondary anti-inflammatory mechanisms of the commonly used cysLTR1 antagonists are the major focus of the current review, which also includes a comparison of the anti-inflammatory effects of montelukast, pranlukast, and zafirlukast on human neutrophilsin vitro, as well as an overview of both the current clinical applications of these agents and potential future applications based on preclinical and early clinical studies.

scholarly journals Protein Kinase Cα-dependent Phosphorylation of the mRNA-stabilizing Factor HuR: Implications for Posttranscriptional Regulation of Cyclooxygenase-2

2007 ◽  
Vol 18 (6) ◽  
pp. 2137-2148 ◽  
Author(s):  
Anke Doller ◽  
Andrea Huwiler ◽  
Roswitha Müller ◽  
Heinfried H. Radeke ◽  
Josef Pfeilschifter ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Mesangial Cells ◽  
Direct Interaction ◽  
Prostaglandin E ◽  
Mobility Shift ◽  
Subsequent Increase ◽  
Cox 2

In this study, we investigated the molecular mechanisms underlying the ATP analogue adenosine-5′-O-(3-thio)triphosphate–induced nucleocytoplasmic shuttling of the mRNA stabilizing factor HuR in human (h) mesangial cells (MC). Using synthetic protein kinase C (PKC) inhibitors and small interfering RNA approaches, we demonstrated that knockdown of PKCα efficiently blocked the ATP-dependent nuclear HuR export to the cytoplasm. The functional importance of PKCα in HuR shuttling is highlighted by the high cytosolic HuR content detected in hMC stably overexpressing PKCα compared with mock-transfected cells. The ATP-induced recruitment of HuR to the cytoplasm is preceded by a direct interaction of PKCα with nuclear HuR and accompanied by increased Ser phosphorylation as demonstrated by coimmunoprecipitation experiments. Mapping of putative PKC target sites identified serines 158 and 221 as being indispensable for HuR phosphorylation by PKCα. RNA pull-down assay and RNA electrophoretic mobility shift assay demonstrated that the HuR shuttling by ATP is accompanied by an increased HuR binding to cyclooxygenase (COX)-2 mRNA. Physiologically, the ATP-dependent increase in RNA binding is linked with an augmentation in COX-2 mRNA stability and subsequent increase in prostaglandin E2 synthesis. Regulation of HuR via PKCα-dependent phosphorylation emphasizes the importance of posttranslational modification for stimulus-dependent HuR shuttling.

Regulation of the membrane-localized prostaglandin E synthases mPGES-1 and mPGES-2 in cardiac myocytes and fibroblasts

2005 ◽  
Vol 288 (1) ◽  
pp. H165-H174 ◽  
Author(s):  
Giovanna Giannico ◽  
Mariela Mendez ◽  
Margot C. LaPointe
Keyword(s):  
Cardiac Myocytes ◽  
P38 Mapk ◽  
Ventricular Myocytes ◽  
Primary Cultures ◽  
Cell Types ◽  
Prostaglandin E ◽  
Western Blots ◽  
Jun Kinase ◽  
Cox 2 ◽  
Perinuclear Area

The proinflammatory mediator cyclooxygenase (COX)-2 and its product PGE2 are induced in the ischemic heart, contributing to inflammatory cell infiltration, fibroblast proliferation, and cardiac hypertrophy. PGE2 synthesis coupled to COX-2 involves two membrane-localized PGE synthases, mPGES-1 and mPGES-2; however, it is not clear how these synthases are regulated in cardiac myocytes and fibroblasts. To study this, we used primary cultures of neonatal ventricular myocytes (VM) and fibroblasts (VF) treated with IL-1β for 24 h. To test for involvement of MAPKs in IL-1β regulation of mPGES-1 and-2, cells were pretreated with the pharmacological inhibitors of p42/44 MAPK, p38 MAPK, and c-Jun kinase (JNK). mRNA was analyzed by RT-PCR. Protein was analyzed by densitometry of Western blots. mPGES-1 was undetectable in untreated VF but induced by IL-1β; inhibition of either p42/44 MAPK or JNK, but not p38 MAPK, was almost completely inhibitory. In VM, inhibition of the three MAPKs reduced IL-1β-stimulated mPGES-1 protein by 70–90%. mPGES-2 was constitutively synthesized in both VM and VF and was not regulated by IL-1β or MAPKs. Confocal microscopy revealed colocalization of both mPGES-1 and mPGES-2 with COX-2 in the perinuclear area of both VF and VM. Finally, PGE2 production was higher in VM than VF. Our data show that 1) mPGES-1 is induced in both VF and VM, 2) regulation of mPGES-1 by MAPK family members is different in the two cell types, 3) mPGES-2 is constitutively synthesized in both VM and VF and is not regulated, and 4) mPGES-1 and mPGES-2 are colocalized with COX-2 in both cells. Thus differences in activity of mPGES-1 and COX-2 or coupling of COX-2 with mPGES-1 may contribute to differences in PGE2 production by myocytes and fibroblasts.

scholarly journals Fish macrophages express a cyclo-oxygenase-2 homologue after activation

1999 ◽  
Vol 340 (1) ◽  
pp. 153-159 ◽  
Author(s):  
Jun ZOU ◽  
Norman F. NEUMANN ◽  
Jason W. HOLLAND ◽  
Miodrag BELOSEVIC ◽  
Charles CUNNINGHAM ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Reading Frame ◽  
Goldfish Carassius Auratus ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Multiple Copies ◽  
Cox 2 ◽  
Inhibitor Of Protein Synthesis ◽  
Cox 1

In mammals, the increased generation of prostaglandins (PG) during the onset of inflammatory responses and activation of immune cell types has been attributed to the induction of a novel cyclo-oxygenase (COX) isoform, termed COX-2, which is distinct from the well-characterized constitutive activity (COX-1). Goldfish (Carassius auratus) macrophages exposed to bacterial lipopolysaccharide and leucocyte-derived macrophage-activating factor(s) showed a significant increase in the generation of the major COX product, PGE2, within the first 6 h of stimulation. The selective COX-2 inhibitor, NS398, inhibited this elevated generation of PGE, whereas the basal level of this product synthesized by unstimulated macrophages was unaffected by such exposure. PGE generation by goldfish macrophages was similarly inhibited by the glucocorticoid, dexamethasone, and an inhibitor of protein synthesis, cycloheximide, suggesting that this stimulation may be due to an inducible enzyme equivalent to mammalian COX-2. The complete coding sequence of rainbow trout (Oncorhynchus mykiss) COX-2 was obtained by PCR. The gene contains a 61 bp 5ʹ-untranslated region (UTR), a 1821 bp open reading frame and a 771 bp 3ʹUTR containing multiple copies of an mRNA instability motif (ATTTA). The predicted translation product had high homology to known mammalian and chicken COX-2 (83-84%) and COX-1 (77%) sequences. Reverse-transcriptase PCR with cDNA from control and bacterially challenged fish revealed that trout COX-2 expression was not constitutive but could be induced. Overall, these studies show for the first time that the inducible isoform of COX has a long evolutionary history, probably dating back to the evolution of fish over 500 million years ago.

scholarly journals The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1044
Author(s):  
Yun Ge ◽  
Man Huang ◽  
Yong-ming Yao
Keyword(s):  
Immune Cells ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
High Mobility ◽  
Cell Types ◽  
High Mobility Group ◽  
High Mobility Group Protein

High mobility group box-1 protein (HMGB1), a member of the high mobility group protein superfamily, is an abundant and ubiquitously expressed nuclear protein. Intracellular HMGB1 is released by immune and necrotic cells and secreted HMGB1 activates a range of immune cells, contributing to the excessive release of inflammatory cytokines and promoting processes such as cell migration and adhesion. Moreover, HMGB1 is a typical damage-associated molecular pattern molecule that participates in various inflammatory and immune responses. In these ways, it plays a critical role in the pathophysiology of inflammatory diseases. Herein, we review the effects of HMGB1 on various immune cell types and describe the molecular mechanisms by which it contributes to the development of inflammatory disorders. Finally, we address the therapeutic potential of targeting HMGB1.

scholarly journals The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1280 ◽  
Author(s):  
Alessandro Maglione ◽  
Simona Rolla ◽  
Stefania Federica De Mercanti ◽  
Santina Cutrupi ◽  
Marinella Clerico
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Adaptive Immune System ◽  
Cell Types ◽  
Point Of View ◽  
Adaptive Immune ◽  
Future Path

Multiple sclerosis (MS) is a chronic central nervous system inflammatory disease that leads to demyelination and neurodegeneration. The third trimester of pregnancy, which is characterized by high levels of estrogens, has been shown to be associated with reduced relapse rates compared with the rates before pregnancy. These effects could be related to the anti-inflammatory properties of estrogens, which orchestrate the reshuffling of the immune system toward immunotolerance to allow for fetal growth. The action of these hormones is mediated by the transcriptional regulation activity of estrogen receptors (ERs). Estrogen levels and ER expression define a specific balance of immune cell types. In this review, we explore the role of estradiol (E2) and ERs in the adaptive immune system, with a focus on estrogen-mediated cellular, molecular, and epigenetic mechanisms related to immune tolerance and neuroprotection in MS. The epigenome dynamics of immune systems are described as key molecular mechanisms that act on the regulation of immune cell identity. This is a completely unexplored field, suggesting a future path for more extensive research on estrogen-induced coregulatory complexes and molecular circuitry as targets for therapeutics in MS.

ceRNA network development and tumor-infiltrating immune cell analysis in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Li Chen ◽  
Weijie Zou ◽  
Lei Zhang ◽  
Huijuan Shi ◽  
Zhi Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Expression Patterns ◽  
Cell Types ◽  
High Morbidity ◽  
Clinical Prognosis ◽  
Cerna Network ◽  
Kaplan Meier

Abstract Background: Hepatocellular carcinoma is among the primary causes of cancer deaths globally. Despite efforts to understand liver cancer, its high morbidity and mortality remain high. Herein, we constructed two nomograms based on ceRNA networks and invading immune cells to describe the molecular mechanisms along with the clinical prognosis of HCC patients.Methods: RNA maps of tumors and normal samples were downloaded from TCGA. HTseq counts and fragments per megapons per thousand bases were read from 421 samples, including 371 tumor samples and 50 normal samples. We established a ceRNA network based on differential gene expression in normal versus tumor subjects. CIBERSORT was employed to differentiate 22 immune cell types according to tumor transcriptomes. Kaplan-Meier along with Cox proportional hazard analyses were employed to determine the prognosis-linked factors. Nomograms were constructed based on prognostic immune cells and ceRNAs. We employed ROC (Receiver operating characteristic) and calibration curve analyses to estimate these nomogram. Results: The difference analysis found 2028 mRNAs, 128 miRNAs, and 136 lncRNAs to be significantly differentially expressed in tumor samples relative to normal samples. We set up a ceRNA network containing 21 protein-coding mRNAs, 12 miRNAs, and 3 lncRNAs. In kaplan-Meier analysis, 21 of the 36 ceRNAs were considered significant. Of the 22 cell types, resting dendritic cell levels were markedly different in tumor samples versus normal controls. Calibration and ROC curve analysis of the ceRNA network, as well as immune-infiltration of tumor showed resultful accuracy (three-year survival AUC: 0.691, five-year survival AUC: 0.700; three-years survival AUC: 0.674, five-year survival AUC: 0.694). Our data suggest that Tregs, CD4 T-cells, mast cells, SNHG1, HMMR and hsa-miR-421 are associated with HCC based on ceRNA-immune cells co-expression patterns. Conclusion: On the basis of ceRNA network modeling and immune cell infiltration analysis, our study offers an effective bioinformatics strategy for studying HCC molecular mechanisms and prognosis.

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