Abstract
BackgroundRetinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs) are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA) in mice.Methodology/Principal findingsWe have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRα1 and TRβ to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA) induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFα and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knock-out mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced.Conclusions/significanceSince retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs regulate skin proliferation, differentiation and inflammation in response to these compounds could have not only physiological but also therapeutic implications.
Highlights
The skin, which protects organisms from the external environment, is comprised of a stratified epithelium, the epidermis, separated by a basement membrane from the underlying connective tissue, the dermis
Reduced proliferative response to retinoids in mice lacking thyroid hormone receptors We have previously observed that the skin of knock-out mice lacking TRa1 and TRb, the major TR isoforms that bind thyroid hormones, shows reduced hyperplasia in response to topical treatment with the tumor promoter TPA
To analyze if the reduced hyperplasia in these animals is a consequence of reduced keratinocyte proliferation, BrdU incorporation was examined in paraffin sections of 9-cis-retinoic acid (RA) and TPA-treated skin incubated with an anti-BrdU antibody
Summary
The skin, which protects organisms from the external environment, is comprised of a stratified epithelium, the epidermis, separated by a basement membrane from the underlying connective tissue, the dermis. Skin homeostasis depends upon a strict control of epidermal proliferation and differentiation. Keratinocytes in the basal layer of the epidermis are able to proliferate, differentiating as they move towards the skin surface progressing through three layers, stratum spinosum, stratum granulosum, and stratum corneum in which eventually cells slough off the skin. Retinoids play an important role in skin homeostasis and are widely used in cosmetics and in the treatment of skin disorders [3]. Topical application of retinoic acid (RA) generates epidermal hyperplasia that results from hyperproliferation of basal keratinocytes leading, upon their vectorial migration towards the skin surface, to thickening of the differentiated suprabasal layers [3]. Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs) are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA) in mice
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