Special Issue "Transcriptional Regulation of Pro-Inflammatory Genes"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (30 April 2015)

Special Issue Editor

Guest Editor
Prof. Dr. Ivana Vancurova

Laboratory of Tumor Immunology, Department of Biology, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
Website | E-Mail
Interests: trancriptional regulation; chemokines; cytokines; NFκB; proteasome; cancer immunology

Special Issue Information

Dear Colleagues,

Cytokines, chemokines, their receptors, and other inflammatory mediators are essential for a proper immune response during infection. Yet, their increased expression is a hallmark of chronic inflammatory disorders, metabolic disorders, and many types of cancer, highlighting the need for stringent regulation of pro-inflammatory gene expression. The nuclear factor-κB (NFκB) family of transcription factors is a central coordinator of the pro-inflammatory gene expression.

While tremendous progress has been made in understanding the pathways and mechanisms leading to NFkB activation, many unanswered questions remain regarding the mechanisms responsible for selectivity and termination of NFκB responses, modulation of NFκB-dependent transcription by post-translational modification of NFκB subunits and their interactions with other transcription factors and regulators, and metabolic regulation of inflammatory gene expression.

This issue intends to present original research articles and up-to-date reviews about all aspects of the transcriptional regulation of inflammatory genes, with a special focus on the regulation of NFκB-dependent inflammatory genes in cancer and metabolic disorders.

We look forward to reading your contributions,

Prof. Dr. Ivana Vancurova
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 650 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.


Keywords

  • chemokines
  • cytokines
  • cytokine receptors
  • transcriptional regulation
  • NFκB
  • cancer
  • inflammation
  • metabolic disorders

Published Papers (15 papers)

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Research

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Open AccessArticle Study of Protein Phosphatase 2A (PP2A) Activity in LPS-Induced Tolerance Using Fluorescence-Based and Immunoprecipitation-Aided Methodology
Biomolecules 2015, 5(3), 1284-1301; doi:10.3390/biom5031284
Received: 29 April 2015 / Revised: 3 June 2015 / Accepted: 4 June 2015 / Published: 29 June 2015
PDF Full-text (3584 KB) | HTML Full-text | XML Full-text
Abstract
Protein phosphatase 2A (PP2A) is one of the most abundant intracellular serine/threonine (Ser/Thr) phosphatases accounting for 1% of the total cellular protein content. PP2A is comprised of a heterodimeric core enzyme and a substrate-specific regulatory subunit. Potentially, at least seventy different compositions of
[...] Read more.
Protein phosphatase 2A (PP2A) is one of the most abundant intracellular serine/threonine (Ser/Thr) phosphatases accounting for 1% of the total cellular protein content. PP2A is comprised of a heterodimeric core enzyme and a substrate-specific regulatory subunit. Potentially, at least seventy different compositions of PP2A exist because of variable regulatory subunit binding that accounts for various activity modulating numerous cell functions. Due to the constitutive phosphatase activity present inside cells, a sensitive assay is required to detect the changes of PP2A activity under various experimental conditions. We optimized a fluorescence assay (DIFMU assay) by combining it with prior anti-PP2A immunoprecipitation to quantify PP2A-specific phosphatase activity. It is also known that prior exposure to lipopolysaccharides (LPS) induces “immune tolerance” of the cells to subsequent stimulation. Herein we report that PP2A activity is upregulated in tolerized peritoneal macrophages, corresponding to decreased TNF-α secretion upon second LPS stimulation. We further examined the role of PP2A in the tolerance effect by using PP2ACαl°xl°x;lyM-Cre conditional knockout macrophages. We found that PP2A phosphatase activity cannot be further increased by tolerance. TNF-α secretion from tolerized PP2ACαl°xl°x;lyM-Cre macrophages is higher than tolerized control macrophages. Furthermore, we showed that the increased TNF-α secretion may be due to an epigenetic transcriptionally active signature on the promoter of TNF-α gene rather than regulation of the NFκB/IκB signaling pathway. These results suggest a role for increased PP2A activity in the regulation of immune tolerance. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)

Review

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Open AccessReview Immune Mechanisms Linking Obesity and Preeclampsia
Biomolecules 2015, 5(4), 3142-3176; doi:10.3390/biom5043142
Received: 23 July 2015 / Revised: 7 October 2015 / Accepted: 20 October 2015 / Published: 12 November 2015
Cited by 8 | PDF Full-text (2007 KB) | HTML Full-text | XML Full-text
Abstract
Preeclampsia (PE) is characterized by hypertension occurring after the twentieth week of pregnancy. It is a significant contributor to maternal and perinatal morbidity and mortality in developing countries and its pervasiveness is increasing within developed countries including the USA. However, the mechanisms mediating
[...] Read more.
Preeclampsia (PE) is characterized by hypertension occurring after the twentieth week of pregnancy. It is a significant contributor to maternal and perinatal morbidity and mortality in developing countries and its pervasiveness is increasing within developed countries including the USA. However, the mechanisms mediating the pathogenesis of this maternal disorder and its rising prevalence are far from clear. A major theory with strong experimental evidence is that placental ischemia, resulting from inappropriate remodeling and widening of the maternal spiral arteries, stimulates the release of soluble factors from the ischemic placenta causing maternal endothelial dysfunction and hypertension. Aberrant maternal immune responses and inflammation have been implicated in each of these stages in the cascade leading to PE. Regarding the increased prevalence of this disease, it is becoming increasingly evident from epidemiological data that obesity, which is a state of chronic inflammation in itself, increases the risk for PE. Although the specific mechanisms whereby obesity increases the rate of PE are unclear, there are strong candidates including activated macrophages and natural killer cells within the uterus and placenta and activation in the periphery of T helper cells producing cytokines including TNF-α, IL-6 and IL-17 and the anti-angiogenic factor sFlt-1 and B cells producing the agonistic autoantibodies to the angiotensin type 1 receptor (AT1-aa). This review will focus on the immune mechanisms that have been implicated in the pathogenesis of hypertension in PE with an emphasis on the potential importance of inflammatory factors in the increased risk of developing PE in obese pregnancies. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Figures

Open AccessReview Transcriptional Activation of Inflammatory Genes: Mechanistic Insight into Selectivity and Diversity
Biomolecules 2015, 5(4), 3087-3111; doi:10.3390/biom5043087
Received: 30 July 2015 / Revised: 11 September 2015 / Accepted: 28 October 2015 / Published: 11 November 2015
Cited by 4 | PDF Full-text (263 KB) | HTML Full-text | XML Full-text
Abstract
Acute inflammation, an integral part of host defence and immunity, is a highly conserved cellular response to pathogens and other harmful stimuli. An inflammatory stimulation triggers transcriptional activation of selective pro-inflammatory genes that carry out specific functions such as anti-microbial activity or tissue
[...] Read more.
Acute inflammation, an integral part of host defence and immunity, is a highly conserved cellular response to pathogens and other harmful stimuli. An inflammatory stimulation triggers transcriptional activation of selective pro-inflammatory genes that carry out specific functions such as anti-microbial activity or tissue healing. Based on the nature of inflammatory stimuli, an extensive exploitation of selective transcriptional activations of pro-inflammatory genes is performed by the host to ensure a defined inflammatory response. Inflammatory signal transductions are initiated by the recognition of inflammatory stimuli by transmembrane receptors, followed by the transmission of the signals to the nucleus for differential gene activations. The differential transcriptional activation of pro-inflammatory genes is precisely controlled by the selective binding of transcription factors to the promoters of these genes. Among a number of transcription factors identified to date, NF-κB still remains the most prominent and studied factor for its diverse range of selective transcriptional activities. Differential transcriptional activities of NF-κB are dictated by post-translational modifications, specificities in dimer formation, and variability in activation kinetics. Apart from the differential functions of transcription factors, the transcriptional activation of selective pro-inflammatory genes is also governed by chromatin structures, epigenetic markers, and other regulators as the field is continuously expanding. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview The Role of the Transcriptional Regulation of Stromal Cells in Chronic Inflammation
Biomolecules 2015, 5(4), 2723-2757; doi:10.3390/biom5042723
Received: 14 August 2015 / Revised: 23 September 2015 / Accepted: 9 October 2015 / Published: 16 October 2015
Cited by 2 | PDF Full-text (849 KB) | HTML Full-text | XML Full-text
Abstract
Chronic inflammation is a common process connecting pathologies that vary in their etiology and pathogenesis such as cancer, autoimmune diseases, and infections. The response of the immune system to tissue damage involves a carefully choreographed series of cellular interactions between immune and non-immune
[...] Read more.
Chronic inflammation is a common process connecting pathologies that vary in their etiology and pathogenesis such as cancer, autoimmune diseases, and infections. The response of the immune system to tissue damage involves a carefully choreographed series of cellular interactions between immune and non-immune cells. In recent years, it has become clear that stromal resident cells have an essential role perpetuating the inflammatory environment and dictating in many cases the outcome of inflammatory based pathologies. Signal transduction pathways remain the main focus of study to understand how stimuli contribute to perpetuating the inflammatory response, mainly due to their potential role as therapeutic targets. However, molecular events orchestrated in the nucleus by transcription factors add additional levels of complexity and may be equally important for understanding the phenotypic differences of activated stromal components during the chronic inflammatory process. In this review, we focus on the contribution of transcription factors to the selective regulation of inducible proinflammatory genes, with special attention given to the regulation of the stromal fibroblastic cell function and response. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Splicing Regulation of Pro-Inflammatory Cytokines and Chemokines: At the Interface of the Neuroendocrine and Immune Systems
Biomolecules 2015, 5(3), 2073-2100; doi:10.3390/biom5032073
Received: 22 April 2015 / Accepted: 28 August 2015 / Published: 7 September 2015
Cited by 2 | PDF Full-text (2299 KB) | HTML Full-text | XML Full-text
Abstract
Alternative splicing plays a key role in posttranscriptional regulation of gene expression, allowing a single gene to encode multiple protein isoforms. As such, alternative splicing amplifies the coding capacity of the genome enormously, generates protein diversity, and alters protein function. More than 90%
[...] Read more.
Alternative splicing plays a key role in posttranscriptional regulation of gene expression, allowing a single gene to encode multiple protein isoforms. As such, alternative splicing amplifies the coding capacity of the genome enormously, generates protein diversity, and alters protein function. More than 90% of human genes undergo alternative splicing, and alternative splicing is especially prevalent in the nervous and immune systems, tissues where cells need to react swiftly and adapt to changes in the environment through carefully regulated mechanisms of cell differentiation, migration, targeting, and activation. Given its prevalence and complexity, this highly regulated mode of gene expression is prone to be affected by disease. In the following review, we look at how alternative splicing of signaling molecules—cytokines and their receptors—changes in different pathological conditions, from chronic inflammation to neurologic disorders, providing means of functional interaction between the immune and neuroendocrine systems. Switches in alternative splicing patterns can be very dynamic and can produce signaling molecules with distinct or antagonistic functions and localization to different subcellular compartments. This newly discovered link expands our understanding of the biology of immune and neuroendocrine cells, and has the potential to open new windows of opportunity for treatment of neurodegenerative disorders. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Macrophage Expression of Inflammatory Genes in Response to EMCV Infection
Biomolecules 2015, 5(3), 1938-1954; doi:10.3390/biom5031938
Received: 16 June 2015 / Revised: 6 August 2015 / Accepted: 8 August 2015 / Published: 18 August 2015
PDF Full-text (679 KB) | HTML Full-text | XML Full-text
Abstract
The expression and production of type 1 interferon is the classic cellular response to virus infection. In addition to this antiviral response, virus infection also stimulates the production of proinflammatory mediators. In this review, the pathways controlling the induction of inflammatory genes and
[...] Read more.
The expression and production of type 1 interferon is the classic cellular response to virus infection. In addition to this antiviral response, virus infection also stimulates the production of proinflammatory mediators. In this review, the pathways controlling the induction of inflammatory genes and the roles that these inflammatory mediators contribute to host defense against viral pathogens will be discussed. Specific focus will be on the role of the chemokine receptor CCR5, as a signaling receptor controlling the activation of pathways leading to virus-induced inflammatory gene expression. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Chromatin Remodeling and Transcriptional Control in Innate Immunity: Emergence of Akirin2 as a Novel Player
Biomolecules 2015, 5(3), 1618-1633; doi:10.3390/biom5031618
Received: 12 May 2015 / Revised: 15 June 2015 / Accepted: 24 June 2015 / Published: 22 July 2015
Cited by 6 | PDF Full-text (4132 KB) | HTML Full-text | XML Full-text
Abstract
Transcriptional regulation of inflammatory gene expression has been at the forefront of studies of innate immunity and is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. The growing evidence for involvement of chromatin in the regulation of gene expression in innate
[...] Read more.
Transcriptional regulation of inflammatory gene expression has been at the forefront of studies of innate immunity and is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. The growing evidence for involvement of chromatin in the regulation of gene expression in innate immune cells, has uncovered an evolutionarily conserved role of microbial sensing and chromatin remodeling. Toll-like receptors and RIG-I-like receptors trigger these signaling pathways leading to transcriptional expression of a set of genes involved in inflammation. Tightly regulated control of this gene expression is a paramount, and often foremost, goal of most biological endeavors. In this review, we will discuss the recent progress about the molecular mechanisms governing control of pro-inflammatory gene expression by an evolutionarily conserved novel nuclear protein Akirin2 in macrophages and its emergence as an essential link between NF-κB and chromatin remodelers for transcriptional regulation. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Roles of Chemokines and Chemokine Receptors in Obesity-Associated Insulin Resistance and Nonalcoholic Fatty Liver Disease
Biomolecules 2015, 5(3), 1563-1579; doi:10.3390/biom5031563
Received: 31 May 2015 / Revised: 6 July 2015 / Accepted: 7 July 2015 / Published: 21 July 2015
Cited by 34 | PDF Full-text (1394 KB) | HTML Full-text | XML Full-text
Abstract
Abundant evidence has demonstrated that obesity is a state of low-grade chronic inflammation that triggers the release of lipids, aberrant adipokines, pro-inflammatory cytokines, and several chemokines from adipose tissue. This low-grade inflammation underlies the development of insulin resistance and associated metabolic comorbidities such
[...] Read more.
Abundant evidence has demonstrated that obesity is a state of low-grade chronic inflammation that triggers the release of lipids, aberrant adipokines, pro-inflammatory cytokines, and several chemokines from adipose tissue. This low-grade inflammation underlies the development of insulin resistance and associated metabolic comorbidities such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). During this development, adipose tissue macrophages accumulate through chemokine (C-C motif) receptor 2 and the ligand for this receptor, monocyte chemoattractant protein-1 (MCP-1), is considered to be pivotal for the development of insulin resistance. To date, the chemokine system is known to be comprised of approximately 40 chemokines and 20 chemokine receptors that belong to the seven-transmembrane G protein-coupled receptor family and, as a result, chemokines appear to exhibit a high degree of functional redundancy. Over the past two decades, the physiological and pathological properties of many of these chemokines and their receptors have been elucidated. The present review highlights chemokines and chemokine receptors as key contributing factors that link obesity to insulin resistance, T2DM, and NAFLD. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Activation of Proinflammatory Responses in Cells of the Airway Mucosa by Particulate Matter: Oxidant- and Non-Oxidant-Mediated Triggering Mechanisms
Biomolecules 2015, 5(3), 1399-1440; doi:10.3390/biom5031399
Received: 18 May 2015 / Revised: 16 June 2015 / Accepted: 16 June 2015 / Published: 2 July 2015
Cited by 23 | PDF Full-text (3314 KB) | HTML Full-text | XML Full-text
Abstract
Inflammation is considered to play a central role in a diverse range of disease outcomes associated with exposure to various types of inhalable particulates. The initial mechanisms through which particles trigger cellular responses leading to activation of inflammatory responses are crucial to clarify
[...] Read more.
Inflammation is considered to play a central role in a diverse range of disease outcomes associated with exposure to various types of inhalable particulates. The initial mechanisms through which particles trigger cellular responses leading to activation of inflammatory responses are crucial to clarify in order to understand what physico-chemical characteristics govern the inflammogenic activity of particulate matter and why some particles are more harmful than others. Recent research suggests that molecular triggering mechanisms involved in activation of proinflammatory genes and onset of inflammatory reactions by particles or soluble particle components can be categorized into direct formation of reactive oxygen species (ROS) with subsequent oxidative stress, interaction with the lipid layer of cellular membranes, activation of cell surface receptors, and direct interactions with intracellular molecular targets. The present review focuses on the immediate effects and responses in cells exposed to particles and central down-stream signaling mechanisms involved in regulation of proinflammatory genes, with special emphasis on the role of oxidant and non-oxidant triggering mechanisms. Importantly, ROS act as a central second-messenger in a variety of signaling pathways. Even non-oxidant mediated triggering mechanisms are therefore also likely to activate downstream redox-regulated events. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Transcription of Interleukin-8: How Altered Regulation Can Affect Cystic Fibrosis Lung Disease
Biomolecules 2015, 5(3), 1386-1398; doi:10.3390/biom5031386
Received: 1 May 2015 / Revised: 19 June 2015 / Accepted: 20 June 2015 / Published: 1 July 2015
Cited by 17 | PDF Full-text (176 KB) | HTML Full-text | XML Full-text
Abstract
Interleukin-8 (IL-8) is a neutrophil chemokine that is encoded on the CXCL8 gene. Normally CXCL8 expression is repressed due to histone deacetylation, octamer-1 binding to the promoter and the inhibitory effect of nuclear factor-κB repressing factor (NRF). However, in response to a suitable
[...] Read more.
Interleukin-8 (IL-8) is a neutrophil chemokine that is encoded on the CXCL8 gene. Normally CXCL8 expression is repressed due to histone deacetylation, octamer-1 binding to the promoter and the inhibitory effect of nuclear factor-κB repressing factor (NRF). However, in response to a suitable stimulus, the human CXCL8 gene undergoes transcription due to its inducible promoter that is regulated by the transcription factors nuclear factor-κB (NF-κB), activating protein (AP-1), CAAT/enhancer-binding protein β (C/EBPβ, also known as NF-IL-6), C/EBP homologous protein (CHOP) and cAMP response element binding protein (CREB). CXCL8 mRNA is then stabilised by the activity of p38 mitogen-activated protein kinase (p38 MAPK). Cystic fibrosis (CF) lung disease is characterised by a neutrophil-dominated airway inflammatory response. A major factor contributing to the large number of neutrophils is the higher than normal levels of IL-8 that are present within the CF lung. Infection and inflammation, together with intrinsic alterations in CF airway cells are responsible for the abnormally high intrapulmonary levels of IL-8. Strategies to inhibit aberrantly high CXCL8 expression hold therapeutic potential for CF lung disease. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Molecular Interactions between NR4A Orphan Nuclear Receptors and NF-κB Are Required for Appropriate Inflammatory Responses and Immune Cell Homeostasis
Biomolecules 2015, 5(3), 1302-1318; doi:10.3390/biom5031302
Received: 30 April 2015 / Revised: 16 June 2015 / Accepted: 16 June 2015 / Published: 29 June 2015
Cited by 11 | PDF Full-text (271 KB) | HTML Full-text | XML Full-text
Abstract
Appropriate innate and adaptive immune responses are essential for protection and resolution against chemical, physical or biological insults. Immune cell polarization is fundamental in orchestrating distinct phases of inflammation, specifically acute phase responses followed by resolution and tissue repair. Dysregulation of immune cell
[...] Read more.
Appropriate innate and adaptive immune responses are essential for protection and resolution against chemical, physical or biological insults. Immune cell polarization is fundamental in orchestrating distinct phases of inflammation, specifically acute phase responses followed by resolution and tissue repair. Dysregulation of immune cell and inflammatory responses is a hallmark of multiple diseases encompassing atherosclerosis, rheumatoid arthritis, psoriasis and metabolic syndromes. A master transcriptional mediator of diverse inflammatory signaling and immune cell function is NF-κB, and altered control of this key regulator can lead to an effective switch from acute to chronic inflammatory responses. Members of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors crosstalk with NF-κB to regulate immune cell function(s). Within the NR superfamily the NR4A1-3 orphan receptors have emerged as important regulators of immune cell polarization and NF-κB signaling. NR4A receptors modulate NF-κB activity in a dynamic fashion, either repressing or enhancing target gene expression leading to altered inflammatory outcome. Here we will discuss the pivotal role NR4A’s receptors play in orchestrating immune cell homeostasis through molecular crosstalk with NF-κB. Specifically, we will examine such NR4A/NF-κB interactions within the context of distinct cell phenotypes, including monocyte, macrophage, T cells, endothelial, and mesenchymal cells, which play a role in inflammation-associated disease. Finally, we review the therapeutic potential of altering NR4A/NF-κB interactions to limit hyper-inflammatory responses in vivo. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Figures

Open AccessReview NF-kappaB Signaling in Chronic Inflammatory Airway Disease
Biomolecules 2015, 5(3), 1266-1283; doi:10.3390/biom5031266
Received: 28 April 2015 / Revised: 31 May 2015 / Accepted: 4 June 2015 / Published: 26 June 2015
Cited by 40 | PDF Full-text (274 KB) | HTML Full-text | XML Full-text
Abstract
Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments. In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression. The
[...] Read more.
Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments. In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression. The redox-sensitive transcription factor, nuclear factor (NF)-kappaB (NF-κB), is an important participant in a broad spectrum of inflammatory networks that regulate cytokine activity in airway pathology. The anti-inflammatory actions of glucocorticoids (GCs), a mainstay treatment for asthma, involve inhibition of NF-κB induced gene transcription. Ligand bound GC receptors (GRs) bind NF-κB to suppress the transcription of NF-κB responsive genes (i.e., transrepression). However, in severe asthma and COPD, the transrepression of NF-κB by GCs is negated as a consequence of post-translational changes to GR and histones involved in chromatin remodeling. Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs) are potential treatments for asthma and COPD. Furthermore, reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-κB transrepression. This review examines NF-κB signaling in airway inflammation and its potential as target for treatment of asthma and COPD. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Transcriptional Regulation of Chemokine Genes: A Link to Pancreatic Islet Inflammation?
Biomolecules 2015, 5(2), 1020-1034; doi:10.3390/biom5021020
Received: 20 April 2015 / Accepted: 12 May 2015 / Published: 26 May 2015
Cited by 7 | PDF Full-text (165 KB) | HTML Full-text | XML Full-text
Abstract
Enhanced expression of chemotactic cytokines (aka chemokines) within pancreatic islets likely contributes to islet inflammation by regulating the recruitment and activation of various leukocyte populations, including macrophages, neutrophils, and T-lymphocytes. Because of the powerful actions of these chemokines, precise transcriptional control is required.
[...] Read more.
Enhanced expression of chemotactic cytokines (aka chemokines) within pancreatic islets likely contributes to islet inflammation by regulating the recruitment and activation of various leukocyte populations, including macrophages, neutrophils, and T-lymphocytes. Because of the powerful actions of these chemokines, precise transcriptional control is required. In this review, we highlight what is known about the signals and mechanisms that govern the transcription of genes encoding specific chemokine proteins in pancreatic islet β-cells, which include contributions from the NF-κB and STAT1 pathways. We further discuss increased chemokine expression in pancreatic islets during autoimmune-mediated and obesity-related development of diabetes. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Extracellular Adenosine Generation in the Regulation of Pro-Inflammatory Responses and Pathogen Colonization
Biomolecules 2015, 5(2), 775-792; doi:10.3390/biom5020775
Received: 11 March 2015 / Revised: 23 April 2015 / Accepted: 25 April 2015 / Published: 5 May 2015
Cited by 6 | PDF Full-text (621 KB) | HTML Full-text | XML Full-text
Abstract
Adenosine, an immunomodulatory biomolecule, is produced by the ecto-enzymes CD39 (nucleoside triphosphate dephosphorylase) and CD73 (ecto-5'-nucleotidase) by dephosphorylation of extracellular ATP. CD73 is expressed by many cell types during injury, infection and during steady-state conditions. Besides host cells, many bacteria also have CD39-CD73-like
[...] Read more.
Adenosine, an immunomodulatory biomolecule, is produced by the ecto-enzymes CD39 (nucleoside triphosphate dephosphorylase) and CD73 (ecto-5'-nucleotidase) by dephosphorylation of extracellular ATP. CD73 is expressed by many cell types during injury, infection and during steady-state conditions. Besides host cells, many bacteria also have CD39-CD73-like machinery, which helps the pathogen subvert the host inflammatory response. The major function for adenosine is anti-inflammatory, and most recent research has focused on adenosine’s control of inflammatory mechanisms underlying various autoimmune diseases (e.g., colitis, arthritis). Although adenosine generated through CD73 provides a feedback to control tissue damage mediated by a host immune response, it can also contribute to immunosuppression. Thus, inflammation can be a double-edged sword: it may harm the host but eventually helps by killing the invading pathogen. The role of adenosine in dampening inflammation has been an area of active research, but the relevance of the CD39/CD73-axis and adenosine receptor signaling in host defense against infection has received less attention. Here, we review our recent knowledge regarding CD73 expression during murine Salmonellosis and Helicobacter-induced gastric infection and its role in disease pathogenesis and bacterial persistence. We also explored a possible role for the CD73/adenosine pathway in regulating innate host defense function during infection. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Transcriptional Regulation of Chemokine Expression in Ovarian Cancer
Biomolecules 2015, 5(1), 223-243; doi:10.3390/biom5010223
Received: 8 December 2014 / Revised: 4 March 2015 / Accepted: 9 March 2015 / Published: 17 March 2015
Cited by 3 | PDF Full-text (7186 KB) | HTML Full-text | XML Full-text
Abstract
The increased expression of pro-inflammatory and pro-angiogenic chemokines contributes to ovarian cancer progression through the induction of tumor cell proliferation, survival, angiogenesis, and metastasis. The substantial potential of these chemokines to facilitate the progression and metastasis of ovarian cancer underscores the need for
[...] Read more.
The increased expression of pro-inflammatory and pro-angiogenic chemokines contributes to ovarian cancer progression through the induction of tumor cell proliferation, survival, angiogenesis, and metastasis. The substantial potential of these chemokines to facilitate the progression and metastasis of ovarian cancer underscores the need for their stringent transcriptional regulation. In this Review, we highlight the key mechanisms that regulate the transcription of pro-inflammatory chemokines in ovarian cancer cells, and that have important roles in controlling ovarian cancer progression. We further discuss the potential mechanisms underlying the increased chemokine expression in drug resistance, along with our perspective for future studies. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title:
Chemokine transcriptional regulation in ovarian cancer
Authors:
Bipradeb Singha and Ivana Vancurova
Affiliation:
Department of Biological Sciences, St. John’s University, 8000 Utopia Parkway, New York, NY 11439, USA; E-Mail: vancuroi@stjohns.edu (I.V.)
Abstract:
The increased expression of pro-inflammatory and pro-angiogenic chemokines contributes to ovarian cancer progression through the induction of tumor cell proliferation, survival, angiogenesis, and metastasis. The substantial potential of these chemokines to facilitate the progression and metastasis of ovarian cancer underscores the need for their stringent transcriptional regulation. In this Review, we highlight the key mechanisms that regulate the transcription of pro-inflammatory chemokines in ovarian cancer cells, and that have important roles in controlling ovarian cancer progression. We further discuss the potential mechanisms underlying the increased chemokine expression in drug resistance, along with our perspective for future studies.

Type of Paper: Review
Title: Chemokine Transcriptional Regulation: A Link to Islet Inflammation
Authors: Susan J. Burke and J. Jason Collier
Affiliation: Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA 70808, USA; E-Mail: Jason.Collier@pbrc.edu (J.C.)
Abstract: Enhanced expression of chemotactic cytokines (aka chemokines) within pancreatic islets contributes to islet inflammation via the recruitment and activation of various leukocyte populations, including macrophages, neutrophils, and T-lymphocytes. The powerful action of these chemokines to regulate islet inflammation is congruent with the need to keep them under precise transcriptional control. In this review, we highlight the key mechanisms that govern the transcription of genes encoding chemokine proteins in pancreatic islet β-cells, which includes emphasis on the NF-κB and STAT1 pathways. We further discuss the implications of increased chemokine expression during autoimmune-mediated and obesity-related development of diabetes.


Type of Paper: Review
Title: Splicing Regulation of Cytokines and Chemokines with Pro-Inflammatory Functions in Normal Conditions and in Disease: at the Interface of the Neuroendocrine and Immune Systems
Author: Matteo Ruggiu
Affiliation: St. John’s University Department of Biological Sciences, St. Albert Hall, Room 202 8000 Utopia Parkway, Queens, NY 11439, USA; E-Mail: ruggium@stjohns.edu
Abstract: Alternative splicing plays a key role in posttranscriptional regulation of gene expression, allowing a single gene to encode multiple protein isoforms. As such, alternative splicing amplifies the coding capacity of the genome enormously, generates protein diversity and alters protein function. More than 90% of human genes undergo alternative splicing, and alternative splicing is especially prevalent in the nervous and immune systems, tissues where cells need to react swiftly and adapt to changes in the environment through carefully regulated mechanisms of cell differentiation, migration, targeting and activation. Given its prevalence and complexity, this highly regulated mode of gene expression is prone to be affected by disease. In the following review we look at how alternative splicing of cytokines and chemokines changes in different pathological conditions, from chronic inflammation to neurologic disorders. Switches in alternative splicing patterns can be very dynamic and can produce cytokines with distinct or antagonistic functions and localized to different subcellular compartments. We also discuss recent studies highlighting how alternative splicing provides a means of functional interaction between the immune and neuroendocrine systems by generating distinctive isoforms of regulatory molecules and by regulating expression of specific splicing factors during stress, cerebral ischemia and diabetes. This newly discovered link expands our understanding of the biology of immune and neuroendocrine cells, and has the potential to open new windows of opportunity for treatment of metabolic and neurodegenerative disorders.

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