Local cortisol activation is involved in EGF-induced immunosuppression

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.

ABSTRACT

The major effects of the epidermal growth factor receptor (EGFR) signalling pathway on keratinocytes are cell proliferation, cell differentiation, and wound healing. In addition to these effects, an immunosuppressive effect of EGFR signalling has been reported. However, the precise mechanism of immunosuppression by EGFR signalling is not well understood.

In this study, we clarified the involvement of increased local cortisol activation in EGFR signalling-induced immunosuppression in keratinocytes.

EGF treatment up-regulated the expression of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and supernatant cortisol levels in a dose-dependent manner in keratinocytes. 11β-HSD1 is an enzyme that catalyses the conversion of cellular hormonally inactive cortisone into active cortisol. qRT-PCR and ELISA assays indicated that EGF significantly decreased tumour necrosis factor α (TNF- α)-induced interleukin-6 (IL-6) expression in keratinocytes. Similarly, 11β-HSD1 overexpression significantly decreased TNF-α-induced IL-6 expression. We evaluated the role of 11β-HSD1 in immunosuppression through EGFR signalling. Blockade of 11β-HSD1 via 11β-HSD1 inhibitor reversed both the expression and production of TNF-α-induced IL-6, which was decreased by EGF in keratinocytes. Therefore, increased local cortisol activation by 11β-HSD1 is involved in EGFR signalling-induced immunosuppression in keratinocytes.

Finally, we evaluated whether EGFR inhibition by cetuximab affects the expression of 11β-HSD1. We found that 0.1 µg cetuximab decreased 11β-HSD1 transcript levels in keratinocytes. The changes in 11β-HSD1 were more apparent in TNF-α-treated cells.

As 11β-HSD1 expression in keratinocytes is associated with inflammation and cell proliferation, this mechanism may be associated with adverse skin reactions observed in patients treated with EGFR inhibitors.

Related collections

Most cited references 20

Record: found
Abstract: found
Article: not found

The epidermal growth factor receptor system in skin repair and inflammation.

Francesca Mascia, Saveria Pastore, Valentina Mariani … (2008)

The epidermal growth factor (EGF) family comprises multiple mediators such as transforming growth factor-alpha, amphiregulin, heparin binding-EGF, and epiregulin, which are crucially involved in the tissue-specific proliferation/differentiation homeostasis. Typically, they act in an autocrine and paracrine manner on their specific cell membrane receptor and mount an effective reparative response to any attack to biophysical integrity. In addition, the EGFR can be activated by transactivation from a variety of G-protein-coupled receptors, integrins, and cytokine receptors, so that it acts as the major transducer of disparate cell functions, including changes in proliferation rate, cellular shape, attachment and motility, and regulation of proinflammatory activation. However, numerous experimental observations indicate that the different EGFR ligands are not redundant, but may rather provide distinct and specific contributions to keratinocyte functions. Importantly, increasing evidence now suggests that the EGFR pathway has a major impact on the inflammatory/immune reactions of the skin, in the apparent effort of enhancing innate immune defense while opposing overactivation of keratinocyte pro-inflammatory functions. This review covers the molecular mechanisms and functions activated by this major growth factor system in the regulation of keratinocyte biology and focuses on the complex contribution of EGFR signaling to the inflammatory processes in the skin.

0 comments Cited 106 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Cortisol synthesis in epidermis is induced by IL-1 and tissue injury.

Sasa Vukelic, Agata Krzyzanowska, Elizabeth Lebrun … (2011)

Glucocorticoids (GCs) are known inhibitors of wound healing. In this study we report the novel finding that both keratinocytes in vitro and epidermis in vivo synthesize cortisol and how this synthesis regulates wound healing. We show that epidermis expresses enzymes essential for cortisol synthesis, including steroid 11 β-hydroxylase (CYP11B1), and an enzyme that controls negative feedback mechanism, 11β-hydroxysteroid dehydrogenase 2 (11βHSD2). We also found that cortisol synthesis in keratinocytes and skin can be stimulated by ACTH and inhibited by metyrapone (CYP11B1 enzyme inhibitor). Interestingly, IL-1β, the first epidermal signal of tissue injury, induces the expression of CYP11B1 and increases cortisol production by keratinocytes. Additionally, we found induction of CYP11B1 increased production of cortisol and activation of GR pathway during wound healing ex vivo and in vivo using human and porcine wound models, respectively. Conversely, inhibition of cortisol synthesis during wound healing increases IL-1β production, suggesting that cortisol synthesis in epidermis may serve as a local negative feedback to proinflammatory cytokines. Local GCs synthesis, therefore, may provide control of the initial proinflammatory response, preventing excessive inflammation upon tissue injury. Inhibition of GC synthesis accelerated wound closure in vivo, providing the evidence that modulation of cortisol synthesis in epidermis may be an important regulatory mechanism during wound healing.

0 comments Cited 48 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Ultraviolet radiation regulates cortisol activity in a waveband-dependent manner in human skin ex vivo.

Michael R Sayre, C Skobowiat, J Dowdy … (2013)

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), and glucocorticoids (GC) and their receptor (GR) play a key role in tissue-specific regulation of GC action. To determine the expression of genes encoding 11β-HSD1 (HSD11B1), 11β-HSD2 (HSD11B2) and GR (GRα; also known as NC3R1) and their protein products, and levels of cortisol in human skin explants and/or cocultured keratinocytes/melanocytes after treatment with ultraviolet (UV) A, B or C wavebands. Skin from foreskins and/or cocultured human keratinocytes/melanocytes were irradiated with UVA, UVB or UVC (skin) and incubated for 12 and 24 h. Methods of reverse transcription-polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay and immunohistochemistry (IHC) were used to determine expression and localization of corresponding genes or antigens. UVB enhanced the HSD11B1 gene and protein expression in a dose-dependent manner, while UVA had no effect. Similarly, UVC increased 11β-HSD1 protein product as measured by IHC. UVB and UVC enhanced cortisol production and decreased epidermal GR expression, while UVA had no detectable effects. Although both UVA and UVB stimulated HSD11B2 gene expression, only UVA increased 11β-HSD2 protein product levels with UVB and UVC having no effect. We suggest that these differential, waveband-dependent effects of UV radiation on the expression of cutaneous HSD11B1, HSD11B2 and GRα genes and their corresponding protein products, and cortisol production are to protect and/or restore the epidermal barrier homeostasis against disruption caused by the elevated cortisol level induced by UVB and UVC. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.

0 comments Cited 43 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Dermatoendocrinol

Journal ID (iso-abbrev): Dermatoendocrinol

Journal ID (publisher-id): KDER

Journal ID (publisher-id): kder20

Title: Dermato-endocrinology

Publisher: Taylor & Francis

ISSN (Print): 1938-1972

ISSN (Electronic): 1938-1980

Publication date Collection: 2017

Publication date (Electronic): 26 December 2017

Publication date PMC-release: 26 December 2017

Volume: 9

Issue: 1

Electronic Location Identifier: e1412018

Affiliations

[a ]Department of Dermatology, Osaka University Graduate School of Medicine , 2-2 Yamadaoka, Suita, Osaka, Japan

[b ]Department of Regenerative Dermatology, Osaka University Graduate School of Medicine , 2-2 Yamadaoka, Suita, Osaka, Japan

Author notes

CONTACT Mika Terao mterao@ 123456derma.med.osaka-u.ac.jp Department of Regenerative Dermatology, Osaka University Graduate School of Medicine , 2-2 Yamadaoka, Suita, 565-0871, Japan

Article

Publisher ID: 1412018

DOI: 10.1080/19381980.2017.1412018

PMC ID: 5821158

PubMed ID: 29484105

SO-VID: bd4b67f1-55ed-4cbd-965c-8fc77e5bef07

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

History

Date received : 7 November 2017

Date accepted : 28 November 2017

Page count

Figures: 3, Tables: 0, Equations: 0, References: 22, Pages: 9

Funding

Funded by: a Grant-in-Aid for Research Activity start-up

Award ID: A16H069520

This work was supported in part by a Grant-in-Aid for Research Activity start-up (A16H069520).

Local cortisol activation is involved in EGF-induced immunosuppression

Read this article at

ABSTRACT

Related collections

Karger: Dermatology

Most cited references 20

The epidermal growth factor receptor system in skin repair and inflammation.

Cortisol synthesis in epidermis is induced by IL-1 and tissue injury.

Ultraviolet radiation regulates cortisol activity in a waveband-dependent manner in human skin ex vivo.

Author and article information

Journal

Affiliations

Author notes

Article

History

Page count

Funding

Categories

Comments

Comment on this article

Similar content 609

Cited by 3

Most referenced authors 196