Dominance of the strongest: Inflammatory cytokines versus glucocorticoids

doi:10.1016/j.cytogfr.2013.12.006

Cytokine & Growth Factor Reviews

Volume 25, Issue 1, February 2014, Pages 21-33

https://doi.org/10.1016/j.cytogfr.2013.12.006 Get rights and content

Abstract

Pro-inflammatory cytokines are involved in the pathogenesis of many inflammatory diseases, and the excessive expression of many of them is normally counteracted by glucocorticoids (GCs), which are steroids that bind to the glucocorticoid receptor (GR). Hence, GCs are potent inhibitors of inflammation, and they are widely used to treat inflammatory diseases, such as asthma, rheumatoid arthritis and inflammatory bowel disease. However, despite the success of GC therapy, many patients show some degree of GC unresponsiveness, called GC resistance (GCR). This is a serious problem because it limits the full therapeutic exploitation of the anti-inflammatory power of GCs. Patients with reduced GC responses often have higher cytokine levels, and there is a complex interplay between GCs and cytokines: GCs downregulate pro-inflammatory cytokines while cytokines limit GC action. Treatment of inflammatory diseases with GCs is successful when GCs dominate. But when cytokines overrule the anti-inflammatory actions of GCs, patients become GC insensitive. New insights into the molecular mechanisms of GR-mediated actions and GCR are needed for the design of more effective GC-based therapies.

Introduction

Synthetic glucocorticoids (GCs) are among the most potent and most effective anti-inflammatory drugs. GCs penetrate through the cell membrane and bind to the glucocorticoid receptor (GR), a transcription factor belonging to the family of nuclear receptors. Upon ligand binding, GR translocates to the nucleus, where the activated GR can either transactivate or transrepress specific genes. Transactivation of GR is predominantly mediated by binding of GR dimers to GC response elements (GRE) in the promoter region of GC-responsive genes, followed by recruitment of coregulators and induction of gene transcription. In addition, GR positively affects gene transcription by DNA-independent mechanisms. Next to transactivation, GR has also transrepressive capacities. The best known mechanisms of transrepression are the protein–protein interactions between monomeric GR and other transcription factors, such as NFκB and AP1. Thus, GR mediates either positive or negative transcriptional events, which together culminate in coordinated anti-inflammatory actions [1], [2].

Owing to their strong anti-inflammatory properties, GCs are often used for the treatment of many inflammatory and autoimmune diseases. However, despite the success of GC therapy, two major drawbacks are associated with the prolonged use of GCs. First, GC therapy is often accompanied by a wide range of detrimental side effects, such as osteoporosis and diabetes [3]. In addition, subpopulations of patients display partial or complete lack of response to GCs, referred to as GC resistance (GCR) [4]. The incidence of GCR is dependent on the inflammatory environment. Several inflammatory diseases, including sepsis, chronic obstructive pulmonary disease (COPD) and cystic fibrosis, seem to be largely steroid resistant, whereas only a minority of patients suffering from asthma, inflammatory bowel disease or rheumatoid arthritis respond poorly to the beneficial effects of GCs.

GCR is a serious clinical problem because it hampers the full therapeutic exploitation of the anti-inflammatory properties of GCs. Patients suffering from inflammatory diseases are often treated with alternative broad-spectrum anti-inflammatory therapies, although all of them are also likely to have serious side effects. An alternative treatment strategy is to reverse GCR by blocking the mechanisms causing it. Hence, detailed knowledge of the physiological actions of GCs and of the negative effects on these is crucial. We review the current knowledge of the mechanisms that participate in GR signaling and how they contribute to GC sensitivity or insensitivity. As inflammatory cytokines, such as TNF, and their respective signaling pathways play crucial roles in the pathology of most immune diseases and as these may inhibit GR function [5], [6], we will discuss these mechanisms of GCR in detail. We believe that understanding the effects of inflammatory cytokines on GR signaling and the mechanisms of these effects may reveal novel therapeutic targets for reversal of GCR.

Section snippets

GC biosynthesis and metabolism

GCs are a class of stress-induced steroid hormones synthesized by the adrenal cortex. Their production is tightly regulated by the hypothalamic–pituitary–adrenal (HPA) axis, more specifically, by the production of CRH in the hypothalamus and ACTH in the anterior pituitary. GCs are critical for normal physiological function due to their regulatory effects on carbohydrate, lipid and protein metabolism, development, and cell differentiation. In basal conditions, endogenous GCs are secreted in a

Inflammation-mediated mechanisms of reduced GC actions

Reduced responses to the beneficial anti-inflammatory effects of GCs may result from defects at different levels of the physiological actions of GCs/GR, including reduced GC binding to GR, lower GR expression, impaired nuclear translocation, reduced ability of GR to bind DNA, and altered cofactor activity. These events can be modulated by inflammatory cytokines and their signaling pathways, which may lead to a weak clinical response to GC therapy of inflammatory diseases. We review here the

GC insensitivity in inflammatory diseases

GCs are the most effective treatment for many inflammatory diseases. However, the occurrence of GC insensitivity in several inflammatory diseases suggests that inflammatory mediators modulate the cellular response to GCs. As mentioned above, inflammatory cytokines may promote the development of steroid insensitivity. As various cell types and cytokines are involved in the pathogenesis of inflammatory diseases, the mechanisms contributing to decreased GC sensitivity for a disease are

Therapeutic implications

Given the effect of different pro-inflammatory cytokines and their signaling pathways on GR function (Fig. 1), consideration should be given to the possibility of therapies directed at immunoregulatory cytokines. In this way, the use of additional treatments to restore the therapeutic effect of GCs represents a double-barrel approach to reducing inflammation: blocking the inflammatory pathway and enhancing the anti-inflammatory actions of GR. Interestingly, the use of inflammatory blockers, by

Conclusions and future perspectives

We have clearly documented that GR function can be negatively modulated under pro-inflammatory conditions (Fig. 1 and Table 1). A more detailed understanding of the molecular mechanisms of GR action and inaction may reveal new drug targets that could be exploited to sensitize resistant diseases to the anti-inflammatory effects of GCs. In addition, there is a need for specific biomarkers to identify patients who are likely to benefit from new therapies. Most current therapeutic strategies are

Disclosure statement

The authors have nothing to disclose.

Lien Dejager finished her PhD in Biotechnology from the University of Ghent in 2010 under the promotership of Prof. Claude Libert, IRC, VIB. Afterwards she became a postdoctoral researcher at FWO-Vlaanderen in the same group. Her major research interests are elucidating the anti-inflammatory mechanisms of glucocorticoids and the mechanisms underlying glucocorticoid resistance, aiming to design more efficient glucocorticoid-based therapies.

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Sofie Vandevyver is a Post-doctoral researcher in Prof. Dr. Claude Libert's Lab in the Inflammation Research Center, University of Ghent. She obtained a degree in Biochemistry from the ‘Hogeschool West-Vlaanderen’, after which she obtained a degree in Biotechnology from the University of Ghent. She started her PhD in the IRC in 2009 after obtaining a fellowship from the Flemish Government Agency for Innovation by Science and Technology (IWT) and finished in 2013. Her research is mainly focused on unraveling the mechanisms of Glucocorticoid Receptor Function, predominantly transactivation, and Glucocorticoid Receptor Resistance in inflammation.

Ioanna Petta is a PhD student in a shared project between the Lab of Mouse Genetics in Inflammation (MGI) of Prof. Claude Libert in the Inflammation Research Center (IRC) and the Cytokine Receptor Lab (CRL) of Prof. Jan Tavernier, University of Gent-VIB. She obtained her Bachelor degree in Biology from the University of Patras (Greece), after which she conducted her Master in Biotechnology in the same University. She started her PhD in 2010 after obtaining a fellowship from the VIB for international PhD students. Her research is focused on the identification and functional analysis of novel interaction partners of the Glucocorticoid receptor in inflammation.

Claude Libert is a full professor at University Ghent and a Group leader at VIB. He obtained his PhD in 1993 and did a postdoc in the IRBM, Rome, Italy, with Valeria Poli and Gennaro Ciliberto during 1994–1995. In 1997 he became VIB group leader. His interest lies mainly in sepsis and other acute inflammatory conditions. His group wants to find new insights in sepsis and is focusing on TNF, MMPs and glucocorticcoids to achieve their goals.

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SurveyDominance of the strongest: Inflammatory cytokines versus glucocorticoids

Abstract

Introduction

Section snippets

GC biosynthesis and metabolism

Inflammation-mediated mechanisms of reduced GC actions

GC insensitivity in inflammatory diseases

Therapeutic implications

Conclusions and future perspectives

Disclosure statement

Lancet

Current Opinion in Pharmacology

Journal of Biological Chemistry

Journal of Biological Chemistry

Cell

Biochimica et Biophysica Acta

Molecular Cell

Journal of Steroid Biochemistry and Molecular Biology

Journal of Biological Chemistry

Cell

Molecular and Cellular Endocrinology

Progress in Brain Research

Brain Research Bulletin

Chest

Biochemical and Biophysical Research Communications

Journal of Biological Chemistry

Steroids

Molecular and Cellular Endocrinology

Current Opinion in Pharmacology

Molecular Cell

Journal of Allergy and Clinical Immunology

Journal of Biological Chemistry

Biochemical and Biophysical Research Communications

Molecular Cell

Molecular and Cellular Endocrinology

New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation

Endocrinology

Antiinflammatory action of glucocorticoids – new mechanisms for old drugs

New England Journal of Medicine

The epidemiology of glucocorticoid-associated adverse events

Current Opinion in Rheumatology

Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor

Journal of Clinical Endocrinology and Metabolism

Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance

Proceedings of the National Academy of Sciences of the United States of America

The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration

Nature Reviews Neuroscience

On the trail of the glucocorticoid receptor: into the nucleus and back

Traffic

Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases

Endocrine Reviews

RSUME enhances glucocorticoid receptor SUMOylation and transcriptional activity

Molecular and Cellular Biology

Cross talk of signaling pathways in the regulation of the glucocorticoid receptor function

Molecular Endocrinology

Inhibition of glucocorticoid receptor binding by nitric oxide

Molecular Pharmacology

Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications

FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology

Glucocorticoid modulation of cytokine signaling

Tissue Antigens

Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements

Genome Research

Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression

Journal of Experimental Medicine

The type I interferon signaling pathway is a target for glucocorticoid inhibition

Molecular and Cellular Biology

The structural basis of direct glucocorticoid-mediated transrepression

Nature Structural & Molecular Biology

Chromatin remodeling complexes interact dynamically with a glucocorticoid receptor-regulated promoter

Molecular Biology of the Cell

Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes

Genome Research

Genetic, functional and molecular features of glucocorticoid receptor binding

PLoS One

Chromatin accessibility pre-determines glucocorticoid receptor binding patterns

Nature Genetics

C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements

The EMBO Journal

Molecular properties of corticosteroid binding globulin and the sex-steroid binding proteins

Survey
Dominance of the strongest: Inflammatory cytokines versus glucocorticoids