Altered skin development and impaired proliferative and inflammatory responses in transgenic mice overexpressing the glucocorticoid receptor

Glucocorticoids (GCs) are potent inhibitors of epidermal proliferation and effective antiinflammatory compounds, which make them the drug of choice fo r a wide range of inflammatory and hyperproliferative skin disorders. GC ac tion is mediated via the glucocorticoid receptor (GR). To study the role of GR in skin development and the molecular mechanisms underlying its action, we generated transgenic mice overexpressing GR in epidermis and other stra tified epithelia, under the control of the keratin K5 promoter. Newborn mic e show altered skin development, manifested as variable-sized skin lesions that range from epidermal hypoplasia and underdeveloped dysplastic hair fol licles to a complete absence of this tissue. In the most affected individua ls, skin was absent at the cranial and umbilical regions, and the vibrissae and eyebrows appear scarce, short, and curly. In addition, as a consequenc e of transgene expression in other ectodermally derived epithelia, K5-GR mi ce exhibited further abnormalities that strikingly resemble the clinical fi ndings in patients with ectodermal dysplasia, which includes aplasia cutis congenita. In adult transgenic skin, topical application of the tumor promo ter TPA did not elicit hyperplasia or transcriptional induction of several proinflammatory cytokines. This antiinflammatory role of GR was due at leas t in part to interference with NF-kappaB, leading to a strong reduction in the kappaB-binding activity without altering the transcriptional levels of the inhibitor I kappaB alpha.