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      Local corticosterone activation by 11β-hydroxysteroid dehydrogenase 1 in keratinocytes: the role in narrow-band UVB-induced dermatitis

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          ABSTRACT

          Keratinocytes are known to synthesize cortisol through activation of the enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). To confirm the function of 11β-HSD1 in keratinocytes during inflammation in vivo, we created keratinocyte-specific-11β-HSD1 knockout mice ( K5-Hsd11b1-KO mice) and analyzed the response to narrow-band ultraviolet B (NB-UVB) irradiation. Firstly, we measured the mRNA and protein levels of 11β-HSD1 following NB-UVB irradiation and found that the expression of 11β-HSD1 in keratinocytes of mouse ear skin was enhanced at 3 and 24 hours after 250 mJ/cm 2, 500 mJ/cm 2, 1 J/cm 2, and 2 J/cm 2 NB-UVB irradiation. Next, we determined that 24 hours after exposure to 1 J/cm 2 NB-UVB irradiation, the numbers of F4/80-, CD45-, and Gr-1-positive cells were increased in K5-Hsd11b1-KO mice compared to wild type (WT) mice. Furthermore, the expression of the chemokine (C-X-C-motif) ligand 1 (CXCL1) and interleukin (IL)-6 was also significantly enhanced in NB-UVB-irradiated K5-Hsd11b1-KO mice compared with WT mice. In addition, activation of nuclear factor-kappa B (NF-κB) after NB-UVB irradiation was enhanced in K5-Hsd11b1-KO mice compared to that in WT mice. Thus, NB-UVB-induced inflammation is augmented in K5-Hsd11b1-KO mice compared with WT mice. These results indicate that 11β-HSD1 may suppress NB-UVB-induced inflammation via inhibition of NF-κB activation.

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          Key role of CRF in the skin stress response system.

          Theoharis C. Theoharides, Martin D. Tobin, Andrzej T. Slominski … (2013)
          The discovery of corticotropin-releasing factor (CRF) or CRH defining the upper regulatory arm of the hypothalamic-pituitary-adrenal (HPA) axis, along with the identification of the corresponding receptors (CRFRs 1 and 2), represents a milestone in our understanding of central mechanisms regulating body and local homeostasis. We focused on the CRF-led signaling systems in the skin and offer a model for regulation of peripheral homeostasis based on the interaction of CRF and the structurally related urocortins with corresponding receptors and the resulting direct or indirect phenotypic effects that include regulation of epidermal barrier function, skin immune, pigmentary, adnexal, and dermal functions necessary to maintain local and systemic homeostasis. The regulatory modes of action include the classical CRF-led cutaneous equivalent of the central HPA axis, the expression and function of CRF and related peptides, and the stimulation of pro-opiomelanocortin peptides or cytokines. The key regulatory role is assigned to the CRFR-1α receptor, with other isoforms having modulatory effects. CRF can be released from sensory nerves and immune cells in response to emotional and environmental stressors. The expression sequence of peptides includes urocortin/CRF→pro-opiomelanocortin→ACTH, MSH, and β-endorphin. Expression of these peptides and of CRFR-1α is environmentally regulated, and their dysfunction can lead to skin and systemic diseases. Environmentally stressed skin can activate both the central and local HPA axis through either sensory nerves or humoral factors to turn on homeostatic responses counteracting cutaneous and systemic environmental damage. CRF and CRFR-1 may constitute novel targets through the use of specific agonists or antagonists, especially for therapy of skin diseases that worsen with stress, such as atopic dermatitis and psoriasis.
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            11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess.

            Stuart Morgan, Emma McCabe, Laura L. Gathercole … (2014)
            The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11β-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11β-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.
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              Mechanisms of glucocorticoid receptor signaling during inflammation.

              Kathleen Smoak, JOHN CIDLOWSKI (2015)
              Glucocorticoids are among the most widely prescribed anti-inflammatory drugs. They act by binding to the glucocorticoid receptor (GR) that, upon activation, translocates to the nucleus and either stimulates or inhibits gene expression. GR inhibition of many proinflammatory response genes occurs through induction of the synthesis of anti-inflammatory proteins as well as through repression of proinflammatory transcription factors, such as nuclear factor-kappaB (NF-kappaB) or activator protein-1 (AP-1). In this review, we discuss the molecular mechanisms underlying GR inhibition of inflammatory responses, with an emphasis on repression of NF-kappaB and AP-1 and their respective signaling pathways.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Dermatoendocrinol
                Journal ID (iso-abbrev): Dermatoendocrinol
                Journal ID (pmc): KDER
                Title: Dermato-endocrinology
                Publisher: Taylor & Francis
                ISSN (Print): 1938-1972
                ISSN (Electronic): 1938-1980
                Publication date Collection: Jan-Dec 2016
                Publication date (Electronic): 5 January 2016
                Publication date PMC-release: 5 January 2016
                Volume: 8
                Issue: 1
                Electronic Location Identifier: e1119958
                Affiliations
                Department of Dermatology, Graduate School of Medicine, Osaka University , Suita, Osaka, Japan
                Author notes
                CONTACT Mika Terao mterao@ 123456derma.med.osaka-u.ac.jp Department of Dermatology, Graduate School of Medicine, Osaka University , Suita, Osaka, Japan
                [†]

                These authors contributed equally to this work.

                Article
                Publisher ID: 1119958
                DOI: 10.1080/19381980.2015.1119958
                PMC ID: 4862380
                PubMed ID: 27195053
                SO-VID: 31501ed7-0f32-4c6e-86b1-7c5827e6e36d
                Copyright © © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License http://creativecommons.org/licenses/by-nc/3.0/, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                Date received : 27 October 2015
                Date accepted : 6 November 2015
                Page count
                Figures: 4, Tables: 0, References: 48, Pages: 12
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Dermatology
                Keywords: corticosterone,inflammation,keratinocytes,narrow-band uvb,11β-hydroxysteroid dehydrogenase 1
                Data availability:
                ScienceOpen disciplines: Dermatology
                Keywords: corticosterone, inflammation, keratinocytes, narrow-band uvb, 11β-hydroxysteroid dehydrogenase 1

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