Oncotarget

Research Papers:

Sexual dimorphism in atrophic effects of topical glucocorticoids is driven by differential regulation of atrophogene REDD1 in male and female skin

Gleb Baida, Shivani Agarwal, Ben Readhead, Joel T. Dudley and Irina Budunova _

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Abstract

Gleb Baida1, Shivani Agarwal1, Ben Readhead2,3, Joel T. Dudley2 and Irina Budunova1

1 Feinberg School of Medicine, Department of Dermatology, Northwestern University, Chicago, IL, USA

2 Icahn School of Medicine at Mount Sinai, New York, NY, USA

3 Current address: ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA

Correspondence to:

Irina Budunova,email: i-budunova@northwestern.edu

Keywords: glucocorticoid; skin atrophy; REDD1; mTOR; sexual dimorphism

Received: December 05, 2019     Accepted: January 04, 2020     Published: January 28, 2020

ABSTRACT

Topical glucocorticoids, well-known anti-inflammatory drugs, induce multiple adverse effects, including skin atrophy. The sex-specific effects of systemic glucocorticoids are known, but sexual dimorphism of therapeutic and side effects of topical steroids has not been studied. We report here that female and male mice were equally sensitive to the anti-inflammatory effect of glucocorticoid fluocinolone acetonide (FA) in ear edema test. At the same time, females were more sensitive to FA-induced skin atrophy. We recently reported that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. We found that REDD1 was more efficiently activated by FA in females, and that REDD1 knockout significantly protected female but not male mice from skin atrophy. Studies using human keratinocytes revealed that both estradiol and FA induced REDD1 mRNA/protein expression, and cooperated when they were combined at low doses. Chromatin immunoprecipitation analysis confirmed that REDD1 is an estrogen receptor (ER) target gene with multiple estrogen response elements in its promoter. Moreover, experiments with GR and ER inhibitors suggested that REDD1 induction by these hormones was interdependent on functional activity of both receptors. Overall, our results are important for the development of safer GR-targeted therapies suited for female and male dermatological patients.


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