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J. Biol. Chem., Vol. 282, Issue 6, 4021-4034, February 9, 2007

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Novel Genomic Effects of Glucocorticoids in Epidermal Keratinocytes

INHIBITION OF APOPTOSIS, INTERFERON- PATHWAY, AND WOUND HEALING ALONG WITH PROMOTION OF TERMINAL DIFFERENTIATION^*

Olivera Stojadinovic¹, Brian Lee¹², Constantinos Vouthounis, Sasa Vukelic, Irena Pastar, Miroslav Blumenberg³, Harold Brem^¶, and Marjana Tomic-Canic⁴

From the Hospital for Special Surgery, Tissue Repair Laboratory, Tissue Engineering, Regeneration and Repair Program, New York, New York 10021, Department of Dermatology, New York University School of Medicine, New York, New York 10016, and ^¶Wound Healing Program, Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York 10034

Glucocorticoids (GCs) have a long history of use as therapeutic agents for numerous skin diseases. Surprisingly, their specific molecular effects are largely unknown. To characterize GC action in epidermis, we compared the transcriptional profiles of primary human keratinocytes untreated and treated with dexamethasone (DEX) for 1, 4, 24, 48, and 72 h using large scale microarray analyses. The majority of genes were found to be regulated only after 24 h and remained regulated throughout treatment. In addition to regulation of the expected pro-inflammatory genes, we found that GCs regulate cell fate, tissue remodeling, cell motility, differentiation, and metabolism. GCs suppress the expression of essentially all IFN-regulated genes, including IFN receptor and STAT-1, an effect that was previously unknown. GCs also block STAT-1 activation and nuclear translocation. Unexpectedly, GCs induce the expression of anti-apoptotic genes and repress pro-apoptotic ones, preventing UV-induced keratinocyte apoptosis. Consequently, treatment with GCs blocked UV-induced apoptosis of keratinocytes. GCs have profound effect on wound healing by inhibiting cell motility and the expression of the proangiogenic factor, vascular endothelial growth factor. They play an important role in tissue remodeling and scar formation by suppressing the expression of TGF1 and -2 and MMP1, -2, -9, and -10 and inducing TIMP-2. Finally, GCs promote terminal epidermal differentiation while simultaneously inhibiting early stage differentiation. These results provide new insights into the beneficial and adverse effects of GCs in the epidermis, defining the participating genes and mechanisms that coordinate the cellular responses important for GC-based therapies.

Received for publication, June 29, 2006 , and in revised form, October 27, 2006.

^* This work was supported by National Institutes of Health Grants AR45974 (to M. T.-C.), NR08029 (to M. T.-C.), T3207190 (to O. S.), DK59424 (to H. B.), and LM008443 (to H. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 4-8.

¹ These authors contributed equally to this work.

² Present address: Genentech, 1 DNA Way, South San Francisco, CA 94080.

³ Supported by the DeBRA foundation with additional funds from DeBRA-US.

⁴ To whom correspondence should be addressed: Dept. of Dermatology, Weill Medical College of Cornell University, Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, 535 E. 70th St., New York, New York 10021. Tel.: 212-774-7160; Fax: 212-249-2373; E-mail: tomicm{at}hss.edu.

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