5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Glucocorticoids promote CCL20 expression in keratinocytes

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Background

          Glucocorticoids (GCs) are generally envisioned as immunosuppressive, but in conditions such as rosacea and perioral dermatitis they can lead to increased skin inflammation. In lung epithelia, GCs promote expression of the proinflammatory cytokine CCL20, which contributes to steroid‐resistant asthma. In the skin, CCL20 stimulates inflammation by recruiting T helper 17 T lymphocytes and dendritic cells, and is elevated in papulopustular rosacea.

          Objectives

          To understand if, and how, GCs affect CCL20 expression in human keratinocytes. CCL20 expression was assessed by quantitative reverse transcriptase polymerase chain reaction and enzyme‐linked immunosorbent assay.

          Methods

          Selective inhibition of candidate genes and signalling pathways was performed using RNA interference and chemical inhibitors. The binding of activated GC receptor to genomic DNA was determined by chromatin immunoprecipitation, and enhancer activity of genomic sequences was measured with a reporter assay.

          Results

          We found that GC treatment increased CCL20 expression in human keratinocytes and murine skin, both in the undisturbed state and with tumour necrosis factor‐α stimulation. GC repressed proinflammatory signalling pathways, including nuclear factor kappa B and p38/mitogen‐activated protein kinase, but these inhibitory effects were opposed by the direct binding of activated GC receptor to the CCL20 enhancer, promoting CCL20 expression.

          Conclusions

          Viewed together, these findings demonstrate a mechanism by which GCs induce expression of CCL20 in keratinocytes, which may contribute to the inflammation seen in steroid‐exacerbated skin conditions.

          Abstract

          What is already known about this topic?

          • Glucocorticoids (GCs) are generally considered immunosuppressive but can actually worsen some inflammatory skin conditions such as rosacea and perioral dermatitis.

          • In bronchial epithelia, GCs promote the expression of the proinflammatory cytokine CCL20, which contributes to steroid‐insensitive asthma.

          • Increased CCL20 is associated with the inflammation of rosacea, but whether GCs induce its expression in the skin is unknown.

          What does this study add?

          • This study demonstrates that activated GC receptor directly binds the CCL20 enhancer in human keratinocytes to promote its expression.

          What is the translational message?

          • GCs can directly activate the expression of CCL20, which may help explain how topical steroids can worsen skin conditions such as perioral dermatitis and rosacea.

          Linked Comment:  R.F.L. O’Shaughnessy. Br J Dermatol 2021; 185:1091–1092 .

          Related collections

          Most cited references30

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          FIMO: scanning for occurrences of a given motif

          Summary: A motif is a short DNA or protein sequence that contributes to the biological function of the sequence in which it resides. Over the past several decades, many computational methods have been described for identifying, characterizing and searching with sequence motifs. Critical to nearly any motif-based sequence analysis pipeline is the ability to scan a sequence database for occurrences of a given motif described by a position-specific frequency matrix. Results: We describe Find Individual Motif Occurrences (FIMO), a software tool for scanning DNA or protein sequences with motifs described as position-specific scoring matrices. The program computes a log-likelihood ratio score for each position in a given sequence database, uses established dynamic programming methods to convert this score to a P-value and then applies false discovery rate analysis to estimate a q-value for each position in the given sequence. FIMO provides output in a variety of formats, including HTML, XML and several Santa Cruz Genome Browser formats. The program is efficient, allowing for the scanning of DNA sequences at a rate of 3.5 Mb/s on a single CPU. Availability and Implementation: FIMO is part of the MEME Suite software toolkit. A web server and source code are available at http://meme.sdsc.edu. Contact: t.bailey@imb.uq.edu.au; t.bailey@imb.uq.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Integrative annotation of chromatin elements from ENCODE data

            The ENCODE Project has generated a wealth of experimental information mapping diverse chromatin properties in several human cell lines. Although each such data track is independently informative toward the annotation of regulatory elements, their interrelations contain much richer information for the systematic annotation of regulatory elements. To uncover these interrelations and to generate an interpretable summary of the massive datasets of the ENCODE Project, we apply unsupervised learning methodologies, converting dozens of chromatin datasets into discrete annotation maps of regulatory regions and other chromatin elements across the human genome. These methods rediscover and summarize diverse aspects of chromatin architecture, elucidate the interplay between chromatin activity and RNA transcription, and reveal that a large proportion of the genome lies in a quiescent state, even across multiple cell types. The resulting annotation of non-coding regulatory elements correlate strongly with mammalian evolutionary constraint, and provide an unbiased approach for evaluating metrics of evolutionary constraint in human. Lastly, we use the regulatory annotations to revisit previously uncharacterized disease-associated loci, resulting in focused, testable hypotheses through the lens of the chromatin landscape.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease.

              Glucocorticoids are primary stress hormones necessary for life that regulate numerous physiologic processes in an effort to maintain homeostasis. Synthetic derivatives of these hormones have been mainstays in the clinic for treating inflammatory diseases, autoimmune disorders, and hematologic cancers. The physiologic and pharmacologic actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Ligand-occupied GR induces or represses the transcription of thousands of genes through direct binding to DNA response elements, physically associating with other transcription factors, or both. The traditional view that glucocorticoids act through a single GR protein has changed dramatically with the discovery of a large cohort of receptor isoforms with unique expression, gene-regulatory, and functional profiles. These GR subtypes are derived from a single gene by means of alternative splicing and alternative translation initiation mechanisms. Posttranslational modification of these GR isoforms further expands the diversity of glucocorticoid responses. Here we discuss the origin and molecular properties of the GR isoforms and their contribution to the specificity and sensitivity of glucocorticoid signaling in healthy and diseased tissues. Published by Mosby, Inc.
                Bookmark

                Author and article information

                Contributors
                bryansun@health.ucsd.edu
                Journal
                Br J Dermatol
                Br J Dermatol
                10.1111/(ISSN)1365-2133
                BJD
                The British Journal of Dermatology
                John Wiley and Sons Inc. (Hoboken )
                0007-0963
                1365-2133
                17 August 2021
                December 2021
                : 185
                : 6 ( doiID: 10.1111/bjd.v185.6 )
                : 1200-1208
                Affiliations
                [ 1 ] Department of Dermatology Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University Shanghai 200127 China
                [ 2 ] Department of Dermatology University of California San Diego La Jolla CA 92093 USA
                [ 3 ] State Key Laboratory of Oncogenes and Related Genes Renji‐Med X Clinical Stem Cell Research Center Ren Ji Hospital Shanghai 200127 China
                [ 4 ] Department of Dermatology Ruijin Hospital School of Medicine Shanghai Jiaotong University Shanghai 200127 China
                Author notes
                [*] [* ] Correspondence

                Bryan K. Sun.

                Email: bryansun@ 123456health.ucsd.edu

                Author information
                https://orcid.org/0000-0002-0740-0125
                Article
                BJD20594
                10.1111/bjd.20594
                9290737
                34157145
                856217a9-3a67-4027-b648-85155ffdb1d5
                © 2021 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 17 June 2021
                Page count
                Figures: 5, Tables: 0, Pages: 9, Words: 5823
                Funding
                Funded by: LEO Fondet , doi 10.13039/501100012331;
                Award ID: 20‐000506
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 81502718
                Categories
                Translational Research
                Original Articles
                Translational Research
                Custom metadata
                2.0
                December 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:18.07.2022

                Dermatology
                Dermatology

                Comments

                Comment on this article