scholarly journals Minireview: Glucocorticoids in Autoimmunity: Unexpected Targets and Mechanisms

2011 ◽  
Vol 25 (7) ◽  
pp. 1075-1086 ◽  
Author(s):  
Jamie R. Flammer ◽  
Inez Rogatsky
Keyword(s):  
Antiinflammatory Activity ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Cytokine Gene Expression ◽  
Extensive Literature ◽  
Complex Functions ◽  
Numerous Cell ◽  
Autoimmune And Inflammatory Diseases ◽  
Health And Disease ◽  
Synthetic Glucocorticoids

Abstract For decades, natural and synthetic glucocorticoids (GC) have been among the most commonly prescribed classes of immunomodulatory drugs. Their unsurpassed immunosuppressive and antiinflammatory activity along with cost-effectiveness makes these compounds a treatment of choice for the majority of autoimmune and inflammatory diseases, despite serious side effects that frequently accompany GC therapy. The activated GC receptor (GR) that conveys the signaling information of these steroid ligands to the transcriptional machinery engages a number of pathways to ultimately suppress autoimmune responses. Of those, GR-mediated apoptosis of numerous cell types of hematopoietic origin and suppression of proinflammatory cytokine gene expression have been described as the primary mechanisms responsible for the antiinflammatory actions of GC. However, along with the ever-increasing appreciation of the complex functions of the immune system in health and disease, we are beginning to recognize new facets of GR actions in immune cells. Here, we give a brief overview of the extensive literature on the antiinflammatory activities of GC and discuss in greater detail the unexpected pathways, factors, and mechanisms that have recently begun to emerge as novel targets for GC-mediated immunosuppression.

scholarly journals Glucocorticoid receptor modulators CpdX and CpdX-D3 exhibit the same in vivo antiinflammatory activities as synthetic glucocorticoids

2019 ◽  
Vol 116 (28) ◽  
pp. 14191-14199 ◽  
Author(s):  
Guoqiang Hua ◽  
Naimah Zein ◽  
François Daubeuf ◽  
Pierre Chambon
Keyword(s):  
Glucocorticoid Receptor ◽  
Lung Inflammation ◽  
Antiinflammatory Activity ◽  
Inflammatory Diseases ◽  
Collagen Induced Arthritis ◽  
Allergic Lung Inflammation ◽  
Dust Mite ◽  
Receptor Modulators ◽  
Synthetic Glucocorticoids

We previously reported that the nonsteroidal compound CpdX, which was initially characterized 20 y ago as a possible gestagen and, shortly afterward, as a possible drug for treatments of inflammatory diseases, selectively triggers the NFκB/AP1-mediated tethered indirect transrepression function of the glucocorticoid receptor (GR), and could therefore be a selective glucocorticoid receptor agonistic modulator (SEGRAM). We now demonstrate that, upon administration to the mouse, CpdX and one of its deuterated derivatives, CpdX-D3, repress as efficiently as a synthetic glucocorticoid (e.g., Dexamethasone) an induced skin atopic dermatitis, an induced psoriasis-like inflammation, a house dust mite (HDM)-induced asthma-like allergic lung inflammation, a collagen-induced arthritis, an induced ulcerative colitis, and an ovalbumin-induced allergic conjunctivitis. Interestingly, in the cases of an HDM-induced asthma-like allergic lung inflammation and of a collagen-induced arthritis, the CpdX antiinflammatory activity was selectively exerted by one of the two CpdX enantiomers, namely, CpdX(eA) or CpdX-D3(eA).

scholarly journals Nitric Oxide in Health and Disease of the Respiratory System

2004 ◽  
Vol 84 (3) ◽  
pp. 731-765 ◽  
Author(s):  
Fabio L. M. Ricciardolo ◽  
Peter J. Sterk ◽  
Benjamin Gaston ◽  
Gert Folkerts
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Multiple Roles ◽  
Major Advance ◽  
Airway Diseases ◽  
Exhaled Air ◽  
Health And Disease ◽  
Novel Target ◽  
Airway Physiology

During the past decade a plethora of studies have unravelled the multiple roles of nitric oxide (NO) in airway physiology and pathophysiology. In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone. On the other hand, NO derived from iNOS seems to be a proinflammatory mediator with immunomodulatory effects. The concentration of this molecule in exhaled air is abnormal in activated states of different inflammatory airway diseases, and its monitoring is potentially a major advance in the management of, e.g., asthma. Finally, the production of NO under oxidative stress conditions secondarily generates strong oxidizing agents (reactive nitrogen species) that may modulate the development of chronic inflammatory airway diseases and/or amplify the inflammatory response. The fundamental mechanisms driving the altered NO bioactivity under pathological conditions still need to be fully clarified, because their regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways.

scholarly journals ATX expression from GFAP+ cells is essential for embryonic development

2020 ◽  
Author(s):  
Ioanna Sevastou ◽  
Ioanna Ninou ◽  
Vassilis Aidinis
Keyword(s):  
Embryonic Development ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Cellular Functions ◽  
Autoimmune Encephalomyelitis ◽  
Health And Disease ◽  
Genetic Deletion ◽  
Almost All ◽  
G Protein Coupled ◽  
Experimental Autoimmune

AbstractAutotaxin (ATX) is secreted by various type of cells in health and disease and catalyzes the extracellular production of lysophosphatidic acid (LPA). In turn, LPA is a bioactive lysophospholipid promoting a wide array of cellular functions through its multiple G-protein coupled receptors, differentially expressed in almost all cell types. ATX expression has been shown necessary for embryonic development and has been suggested to participate in the pathogenesis of different chronic inflammatory diseases and cancer. Deregulated ATX and LPA levels have been reported in multiple sclerosis (MS) and its experimental model, experimental autoimmune encephalomyelitis (EAE). ATX genetic deletion from macrophages and microglia (CD11b+ cells) attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in MS/EAE. In this report, increased ATX staining was localized to glial fibrillary acidic protein positive (GFAP+) cells, mostly astrocytes, in spinal cord sections from EAE mice at the peak of the disease. However, genetic deletion of ATX from GFAP+ cells resulted in embryonic lethality, suggesting a major role for ΑΤΧ expression from GFAP+ cells in embryonic development, that urges further dissection. Moreover, the re-expression of ATX from GFAP+ cells during the pathogenesis of EAE, reinforces the concept that ATX/LPA is a developmental program aberrantly reactivated upon chronic inflammation.

scholarly journals Tissue-resident lymphocytes: weaponized sentinels at barrier surfaces

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 691 ◽  
Author(s):  
Gabrielle T. Belz ◽  
Renae Denman ◽  
Cyril Seillet ◽  
Nicolas Jacquelot
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Circulatory System ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Mait Cells ◽  
Local Perturbations ◽  
Numerous Cell

Tissue-resident immune cells stably localize in tissues largely independent of the circulatory system. While initial studies have focused on the recognition of CD8+ tissue-resident memory T (CD8 TRM) cells, it is now clear that numerous cell types such as CD4+ T cells, gd T cells, innate lymphoid cells and mucosal-associated invariant T (MAIT) cells form stable populations in tissues. They are enriched at the barrier surfaces and within non-lymphoid compartments. They provide an extensive immune network capable of sensing local perturbations of the body’s homeostasis. This positioning enables immune cells to positively influence immune protection against infection and cancer but paradoxically also augment autoimmunity, allergy and chronic inflammatory diseases. Here, we highlight the recent studies across multiple lymphoid immune cell types that have emerged on this research topic and extend our understanding of this important cellular network. In addition, we highlight the areas that remain gaps in our knowledge of the regulation of these cells and how a deeper understanding may result in new ways to ‘target’ these cells to influence disease outcome and treatments.

scholarly journals The Sophisticated Transcriptional Response Governed by Transposable Elements in Human Health and Disease

2020 ◽  
Vol 21 (9) ◽  
pp. 3201
Author(s):  
Federica Marasca ◽  
Erica Gasparotto ◽  
Benedetto Polimeni ◽  
Rebecca Vadalà ◽  
Valeria Ranzani ◽  
...  
Keyword(s):  
Transposable Elements ◽  
Human Genome ◽  
Regulatory Networks ◽  
Driving Forces ◽  
Inflammatory Diseases ◽  
Transcriptional Response ◽  
Selfish Dna ◽  
Bioinformatic Tools ◽  
Autoimmune And Inflammatory Diseases ◽  
Health And Disease

Transposable elements (TEs), which cover ~45% of the human genome, although firstly considered as “selfish” DNA, are nowadays recognized as driving forces in eukaryotic genome evolution. This capability resides in generating a plethora of sophisticated RNA regulatory networks that influence the cell type specific transcriptome in health and disease. Indeed, TEs are transcribed and their RNAs mediate multi-layered transcriptional regulatory functions in cellular identity establishment, but also in the regulation of cellular plasticity and adaptability to environmental cues, as occurs in the immune response. Moreover, TEs transcriptional deregulation also evolved to promote pathogenesis, as in autoimmune and inflammatory diseases and cancers. Importantly, many of these findings have been achieved through the employment of Next Generation Sequencing (NGS) technologies and bioinformatic tools that are in continuous improvement to overcome the limitations of analyzing TEs sequences. However, they are highly homologous, and their annotation is still ambiguous. Here, we will review some of the most recent findings, questions and improvements to study at high resolution this intriguing portion of the human genome in health and diseases, opening the scenario to novel therapeutic opportunities.

scholarly journals Histone deacetylases as targets for treatment of multiple diseases

2013 ◽  
Vol 124 (11) ◽  
pp. 651-662 ◽  
Author(s):  
Jinhua Tang ◽  
Haidong Yan ◽  
Shougang Zhuang
Keyword(s):  
Histone Deacetylases ◽  
Metabolic Disorders ◽  
Interstitial Fibrosis ◽  
Inflammatory Diseases ◽  
Hdac Inhibitors ◽  
Cell Types ◽  
Immunomodulatory Activity ◽  
Anti Cancer ◽  
Proliferation And Differentiation ◽  
Autoimmune And Inflammatory Diseases

HDACs (histone deacetylases) are a group of enzymes that deacetylate histones as well as non-histone proteins. They are known as modulators of gene transcription and are associated with proliferation and differentiation of a variety of cell types and the pathogenesis of some diseases. Recently, HDACs have come to be considered crucial targets in various diseases, including cancer, interstitial fibrosis, autoimmune and inflammatory diseases, and metabolic disorders. Pharmacological inhibitors of HDACs have been used or tested to treat those diseases. In the present review, we will examine the application of HDAC inhibitors in a variety of diseases with the focus on their effects of anti-cancer, fibrosis, anti-inflammatory, immunomodulatory activity and regulating metabolic disorders.

Role of inflammation in the development of colorectal cancer

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.

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

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