Antimitogenic and mitogenic actions of interleukin-1 in diverse cell types are associated with induction of gro gene expression

The macrophage-derived cytokine interleukin-1 (IL-1) can provide a second signal with antigen to elicit production of interleukin-2 (IL-2) by helper T cells. The pathway(s) involved remains controversial, with protein kinase C and cyclic AMP (cAMP) invoked as possible second messengers. In the murine thymoma EL4.E1, IL-1 could synergize with the phosphoinositide pathway, because the cells made higher levels of IL-2 in the presence of IL-1 than could be induced by phorbol ester plus calcium ionophore alone. IL-1 is unlikely to act through a sustained increase in cAMP in these cells because it did not raise cAMP levels detectably and because IL-1 and forskolin had opposite effects on IL-2 gene expression. Inducible expression of a transfected reporter gene linked to a cloned fragment of the murine IL-2 gene promoter was initially increased by IL-1 costimulation, implying that IL-1 can increase the rate of transcription of IL-2. The minimal promoter elements required for iL-1 responsiveness were located within 321 bp of the IL-2 RNA cap site, and further upstream sequences to -2800 did not modify this response. IL-1 costimulation resulted in enhanced activity of both an inducible NF-kappa B-like factor and one of two distinct AP-1-like factors that bind to IL-2 regulatory sequences. Neither was induced, however, by IL-1 alone. Another AP-1-like factor and NFAT-1, while inducible in other cell types, were expressed constitutively in the EL4.E1 cells and were unaffected by IL-1. These results are discussed in terms of the combinatorial logic of IL-2 gene expression.

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Interleukin-1 synergy with phosphoinositide pathway agonists for induction of interleukin-2 gene expression: molecular basis of costimulation

Molecular and Cellular Biology ◽

10.1128/mcb.10.12.6325-6334.1990 ◽

1990 ◽

Vol 10 (12) ◽

pp. 6325-6334

Author(s):

T J Novak ◽

D Chen ◽

E V Rothenberg

Keyword(s):

Gene Expression ◽

Second Messengers ◽

Interleukin 1 ◽

Interleukin 2 ◽

Calcium Ionophore ◽

Gene Promoter ◽

Cell Types ◽

Regulatory Sequences ◽

Nf Kappa B ◽

Phosphoinositide Pathway

The macrophage-derived cytokine interleukin-1 (IL-1) can provide a second signal with antigen to elicit production of interleukin-2 (IL-2) by helper T cells. The pathway(s) involved remains controversial, with protein kinase C and cyclic AMP (cAMP) invoked as possible second messengers. In the murine thymoma EL4.E1, IL-1 could synergize with the phosphoinositide pathway, because the cells made higher levels of IL-2 in the presence of IL-1 than could be induced by phorbol ester plus calcium ionophore alone. IL-1 is unlikely to act through a sustained increase in cAMP in these cells because it did not raise cAMP levels detectably and because IL-1 and forskolin had opposite effects on IL-2 gene expression. Inducible expression of a transfected reporter gene linked to a cloned fragment of the murine IL-2 gene promoter was initially increased by IL-1 costimulation, implying that IL-1 can increase the rate of transcription of IL-2. The minimal promoter elements required for iL-1 responsiveness were located within 321 bp of the IL-2 RNA cap site, and further upstream sequences to -2800 did not modify this response. IL-1 costimulation resulted in enhanced activity of both an inducible NF-kappa B-like factor and one of two distinct AP-1-like factors that bind to IL-2 regulatory sequences. Neither was induced, however, by IL-1 alone. Another AP-1-like factor and NFAT-1, while inducible in other cell types, were expressed constitutively in the EL4.E1 cells and were unaffected by IL-1. These results are discussed in terms of the combinatorial logic of IL-2 gene expression.

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Spatial organization of endometrial gene expression at the onset of embryo attachment in pigs

BMC Genomics ◽

10.1186/s12864-019-6264-2 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 4

Author(s):

Shuqin Zeng ◽

Susanne E. Ulbrich ◽

Stefan Bauersachs

Keyword(s):

Gene Expression ◽

Blood Vessels ◽

Growth Regulation ◽

Spatial Organization ◽

Interleukin 1 ◽

Differential Expression Analysis ◽

Cell Types ◽

Cell Junction ◽

Endometrial Cell ◽

Filamentous Form

Abstract Background During the preimplantation phase in the pig, the conceptus trophoblast elongates into a filamentous form and secretes estrogens, interleukin 1 beta 2, interferons, and other signaling molecules before attaching to the uterine epithelium. The processes in the uterine endometrium in response to conceptus signaling are complex. Thus, the objective of this study was to characterize transcriptome changes in porcine endometrium during the time of conceptus attachment considering the specific localization in different endometrial cell types. Results Low-input RNA-sequencing was conducted for the main endometrial compartments, luminal epithelium (LE), glandular epithelium (GE), blood vessels (BV), and stroma. Samples were isolated from endometria collected on Day 14 of pregnancy and the estrous cycle (each group n = 4) by laser capture microdissection. The expression of 12,000, 11,903, 11,094, and 11,933 genes was detectable in LE, GE, BV, and stroma, respectively. Differential expression analysis was performed between the pregnant and cyclic group for each cell type as well as for a corresponding dataset for complete endometrium tissue samples. The highest number of differentially expressed genes (DEGs) was found for LE (1410) compared to GE, BV, and stroma (800, 1216, and 384). For the complete tissue, 3262 DEGs were obtained. The DEGs were assigned to Gene Ontology (GO) terms to find overrepresented functional categories and pathways specific for the individual endometrial compartments. GO classification revealed that DEGs in LE were involved in ‘biosynthetic processes’, ‘related to ion transport’, and ‘apoptotic processes’, whereas ‘cell migration’, ‘cell growth’, ‘signaling’, and ‘metabolic/biosynthetic processes’ categories were enriched for GE. For blood vessels, categories such as ‘focal adhesion’, ‘actin cytoskeleton’, ‘cell junction’, ‘cell differentiation and development’ were found as overrepresented, while for stromal samples, most DEGs were assigned to ‘extracellular matrix’, ‘gap junction’, and ‘ER to Golgi vesicles’. Conclusions The localization of differential gene expression to different endometrial cell types provided a significantly improved view on the regulation of biological processes involved in conceptus implantation, such as the control of uterine fluid secretion, trophoblast attachment, growth regulation by Wnt signaling and other signaling pathways, as well as the modulation of the maternal immune system.

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Local mechanisms for acupoint sensitization in gall bladder meridian of foot shaoyang-a gene chip study

Acupuncture & Electro-Therapeutics Research ◽

10.3727/036012919x15650315071898 ◽

2019 ◽

Vol 44 (2) ◽

pp. 77-87

Author(s):

Koichi Ishida ◽

Liyue Qin ◽

Ting Wang ◽

Ying Lei ◽

Weiwei Hu ◽

...

Keyword(s):

Gene Expression ◽

Gall Bladder ◽

Interleukin 1 ◽

Gene Chip ◽

Molecular Evidence ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Bladder Meridian ◽

Integrin Linked Kinase ◽

Necrosis Factor

Acupuncture manipulations are clinically important to traditional Chinese medicine, yet the biological mechanisms have not been fully understood. This study aimed to investigate continuous stimulation-induced gene expression changes at stimulated and non-stimulated adjacent acupoints in the same meridian. Catgut embedding into acupoint (CEP) was conducted at acupoint Yanglingquan (gall bladder meridian of foot-shaoyang 34, GB34) of Sprague Dawley rats once or continuously for eight weeks, and gene expression changes at GB34 were assessed by gene chip array analysis 72 h after the last CEP treatment. A total of 688 genes exhibited opposite changes in expression between the two treatments, and 1,336 genes were regulated only by the eight-week CEP treatment. Ingenuity Pathway Analysis revealed that among these differentially regulated genes by one-time and eight-week CEP treatment, insulin-like growth factor-1 pathway and integrin-linked kinase pathway, and Wnt/~ catenin signaling pathway match the observed gene changes to predicted up/down regulation patterns. Upstream analysis further predicted six molecules, namely, tumor necrosis factor, interleukin 1~, interleukin la, kallikrein-related peptidase 5, protein kinase Ca, and catenin ~1. On the other hand, continuous eight-week CEP stimulation at acupoint Xuanzhong (GB39) caused similar changes in the expression of 32 genes at acupoints GB34 and Fengshi (GB31) on the same meridian. Taken together, our results provide the first molecular evidence for the local acupoints' mechanisms for acupoint sensitization theory, and implicate the existence of signaling pathways, either direct or indirect, between acupoints within the meridian GB.

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Role of inflammation in the development of colorectal cancer

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200909092908 ◽

2020 ◽

Vol 20 ◽

Author(s):

Sridhar Muthusami ◽

R. Ileng Kumaran ◽

Kokelavani Nampalli Babu ◽

Sneha Krishnamoorthy ◽

Akash Guruswamy ◽

...

Keyword(s):

Colorectal Cancer ◽

Chronic Inflammation ◽

Interleukin 1 ◽

Cell Types ◽

Model Systems ◽

Cytokine Gene Expression ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Proinflammatory Molecules

: Chronic inflammation can lead to the development of many diseases including cancer. Inflammatory bowel disease (IBD) that includes both ulcerative colitis (UC) and Crohn's disease (CD) are risk factors for the development of colorectal cancer (CRC). Many cytokines produced primarily by the gut immune cells either during or in response to localized inflammation in the colon and rectum are known to stimulate the complex interactions between the different cell types in the gut environment resulting in acute inflammation. Subsequently, chronic inflammation together with genetic and epigenetic changes has been shown to lead to the development and progression of CRC. Various cell types present in the colon such as enterocytes, Paneth cells, goblet cells and macrophages express receptors for inflammatory cytokines and respond to tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6 and other cytokines. Among the several cytokines produced, TNF-α and IL-1β are the key proinflammatory molecules that play critical roles in the development of CRC. The current review is intended to consolidate the published findings to focus on the role of proinflammatory cytokines, namely TNF-α and IL-1β, on inflammation (and the altered immune response) in the gut, to better understand the development of CRC in IBD, using various experimental model systems, preclinical and clinical studies. Moreover, this review also highlights the current therapeutic strategies available (monotherapy and combination therapy), to alleviate the symptoms or treat inflammationassociated CRC by using monoclonal antibodies or aptamers to block proinflammatory molecules, inhibitors of tyrosine kinases in inflammatory signaling cascade, competitive inhibitors of proinflammatory molecules, and the nucleic acid drugs like small activating RNAs (saRNAs) or microRNA (miRNA) mimics to activate tumor suppressor or repress oncogene/proinflammatory cytokine gene expression.

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Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex

Communications Biology ◽

10.1038/s42003-021-02188-w ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Bastiaan van der Veen ◽

Sampath K. T. Kapanaiah ◽

Kasyoka Kilonzo ◽

Peter Steele-Perkins ◽

Martin M. Jendryka ◽

...

Keyword(s):

Gene Expression ◽

Anterior Cingulate Cortex ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Pyramidal Neurons ◽

Treatment Options ◽

Pyramidal Cells ◽

Cingulate Cortex ◽

Cell Types ◽

Anterior Cingulate

AbstractPathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

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Mitochondrial Glucocorticoid Receptors and Their Actions

International Journal of Molecular Sciences ◽

10.3390/ijms22116054 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6054

Author(s):

Ioanna Kokkinopoulou ◽

Paraskevi Moutsatsou

Keyword(s):

Gene Expression ◽

Glucocorticoid Receptors ◽

Mitochondrial Gene ◽

Cell Types ◽

Ros Generation ◽

Mitochondrial Gene Expression ◽

Mitochondrial Energy Metabolism ◽

Bcl2 Family ◽

Cellular Processes ◽

Almost All

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

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Identifying cell types from single-cell data based on similarities and dissimilarities between cells

BMC Bioinformatics ◽

10.1186/s12859-020-03873-z ◽

2021 ◽

Vol 22 (S3) ◽

Author(s):

Yuanyuan Li ◽

Ping Luo ◽

Yi Lu ◽

Fang-Xiang Wu

Keyword(s):

Gene Expression ◽

Single Cell ◽

Spectral Clustering ◽

Incidence Matrix ◽

Expression Patterns ◽

Cell Types ◽

Clustering Method ◽

Different Types ◽

Cell Data ◽

Spectral Clustering Method

Abstract Background With the development of the technology of single-cell sequence, revealing homogeneity and heterogeneity between cells has become a new area of computational systems biology research. However, the clustering of cell types becomes more complex with the mutual penetration between different types of cells and the instability of gene expression. One way of overcoming this problem is to group similar, related single cells together by the means of various clustering analysis methods. Although some methods such as spectral clustering can do well in the identification of cell types, they only consider the similarities between cells and ignore the influence of dissimilarities on clustering results. This methodology may limit the performance of most of the conventional clustering algorithms for the identification of clusters, it needs to develop special methods for high-dimensional sparse categorical data. Results Inspired by the phenomenon that same type cells have similar gene expression patterns, but different types of cells evoke dissimilar gene expression patterns, we improve the existing spectral clustering method for clustering single-cell data that is based on both similarities and dissimilarities between cells. The method first measures the similarity/dissimilarity among cells, then constructs the incidence matrix by fusing similarity matrix with dissimilarity matrix, and, finally, uses the eigenvalues of the incidence matrix to perform dimensionality reduction and employs the K-means algorithm in the low dimensional space to achieve clustering. The proposed improved spectral clustering method is compared with the conventional spectral clustering method in recognizing cell types on several real single-cell RNA-seq datasets. Conclusions In summary, we show that adding intercellular dissimilarity can effectively improve accuracy and achieve robustness and that improved spectral clustering method outperforms the traditional spectral clustering method in grouping cells.

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What Are the Potential Roles of Nuclear Perlecan and Other Heparan Sulphate Proteoglycans in the Normal and Malignant Phenotype

International Journal of Molecular Sciences ◽

10.3390/ijms22094415 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4415

Author(s):

Anthony J. Hayes ◽

James Melrose

Keyword(s):

Gene Expression ◽

Nuclear Envelope ◽

Annulus Fibrosus ◽

Heparan Sulphate ◽

Cell Types ◽

Malignant Cell ◽

Cytoskeletal Proteins ◽

Nucleus Pulposus Cells ◽

Malignant Phenotype ◽

Heparan Sulphate Proteoglycans

The recent discovery of nuclear and perinuclear perlecan in annulus fibrosus and nucleus pulposus cells and its known matrix stabilizing properties in tissues introduces the possibility that perlecan may also have intracellular stabilizing or regulatory roles through interactions with nuclear envelope or cytoskeletal proteins or roles in nucleosomal-chromatin organization that may regulate transcriptional factors and modulate gene expression. The nucleus is a mechano-sensor organelle, and sophisticated dynamic mechanoresponsive cytoskeletal and nuclear envelope components support and protect the nucleus, allowing it to perceive and respond to mechano-stimulation. This review speculates on the potential roles of perlecan in the nucleus based on what is already known about nuclear heparan sulphate proteoglycans. Perlecan is frequently found in the nuclei of tumour cells; however, its specific role in these diseased tissues is largely unknown. The aim of this review is to highlight probable roles for this intriguing interactive regulatory proteoglycan in the nucleus of normal and malignant cell types.

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Optimizing expression quantitative trait locus mapping workflows for single-cell studies

Genome Biology ◽

10.1186/s13059-021-02407-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Anna S. E. Cuomo ◽

Giordano Alvari ◽

Christina B. Azodi ◽

Davis J. McCarthy ◽

Marc Jan Bonder ◽

...

Keyword(s):

Gene Expression ◽

Quantitative Trait Locus ◽

Single Cell ◽

Quantitative Trait ◽

Cell Types ◽

Expression Quantitative Trait Locus ◽

Eqtl Mapping ◽

Trait Locus ◽

The Impact

Abstract Background Single-cell RNA sequencing (scRNA-seq) has enabled the unbiased, high-throughput quantification of gene expression specific to cell types and states. With the cost of scRNA-seq decreasing and techniques for sample multiplexing improving, population-scale scRNA-seq, and thus single-cell expression quantitative trait locus (sc-eQTL) mapping, is increasingly feasible. Mapping of sc-eQTL provides additional resolution to study the regulatory role of common genetic variants on gene expression across a plethora of cell types and states and promises to improve our understanding of genetic regulation across tissues in both health and disease. Results While previously established methods for bulk eQTL mapping can, in principle, be applied to sc-eQTL mapping, there are a number of open questions about how best to process scRNA-seq data and adapt bulk methods to optimize sc-eQTL mapping. Here, we evaluate the role of different normalization and aggregation strategies, covariate adjustment techniques, and multiple testing correction methods to establish best practice guidelines. We use both real and simulated datasets across single-cell technologies to systematically assess the impact of these different statistical approaches. Conclusion We provide recommendations for future single-cell eQTL studies that can yield up to twice as many eQTL discoveries as default approaches ported from bulk studies.

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