Rapamycin Modulates Glucocorticoid Receptor Function, Blocks Atrophogene REDD1, and Protects Skin from Steroid Atrophy

Ekaterina Lesovaya, Shivani Agarwal, Ben Readhead, Elena Vinokour, Gleb Baida, Pankaj Bhalla, Kirill Kirsanov, Marianna Yakubovskaya, Leonidas C. Platanias, Joel T. Dudley, Irina Budunova

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Glucocorticoids have excellent therapeutic properties; however, they cause significant adverse atrophogenic effects. The mTORC1 inhibitor REDD1 has been recently identified as a key mediator of glucocorticoid-induced atrophy. We performed computational screening of a connectivity map database to identify putative REDD1 inhibitors. The top selected candidates included rapamycin, which was unexpected because it inhibits pro-proliferative mTOR signaling. Indeed, rapamycin inhibited REDD1 induction by glucocorticoids dexamethasone, clobetasol propionate, and fluocinolone acetonide in keratinocytes, lymphoid cells, and mouse skin. We also showed blunting of glucocorticoid-induced REDD1 induction by either catalytic inhibitor of mTORC1/2 (OSI-027) or genetic inhibition of mTORC1, highlighting role of mTOR in glucocorticoid receptor signaling. Moreover, rapamycin inhibited glucocorticoid receptor phosphorylation, nuclear translocation, and loading on glucocorticoid-responsive elements in REDD1 promoter. Using microarrays, we quantified a global effect of rapamycin on gene expression regulation by fluocinolone acetonide in human keratinocytes. Rapamycin inhibited activation of glucocorticoid receptor target genes yet enhanced the repression of pro-proliferative and proinflammatory genes. Remarkably, rapamycin protected skin against glucocorticoid-induced atrophy but had no effect on the glucocorticoid anti-inflammatory activity in different in vivo models, suggesting the clinical potential of combining rapamycin with glucocorticoids for the treatment of inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)1935-1944
Number of pages10
JournalJournal of Investigative Dermatology
Volume138
Issue number9
DOIs
StatePublished - Sep 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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    Lesovaya, E., Agarwal, S., Readhead, B., Vinokour, E., Baida, G., Bhalla, P., Kirsanov, K., Yakubovskaya, M., Platanias, L. C., Dudley, J. T., & Budunova, I. (2018). Rapamycin Modulates Glucocorticoid Receptor Function, Blocks Atrophogene REDD1, and Protects Skin from Steroid Atrophy. Journal of Investigative Dermatology, 138(9), 1935-1944. https://doi.org/10.1016/j.jid.2018.02.045