title: The thyroid hormone receptors modulate the skin response to retinoids.
abstract: BACKGROUND
  Retinoids 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.
  
  
  RESULTS
  We 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
  Since 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.
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: García-Serrano
authors.forename: María Ana
authors.initials: MA
authors.lastname: Gomez-Ferrería
authors.forename: Constanza
authors.initials: C
authors.lastname: Contreras-Jurado
authors.forename: Carmen
authors.initials: C
authors.lastname: Segrelles
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Paramio
authors.forename: Ana
authors.initials: A
authors.lastname: Aranda
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006965:Hyperplasia; D007037:Hypothyroidism / Q000503:physiopathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012176:Retinoids / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D015850:Interleukin-6; D012176:Retinoids; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014409:Tumor Necrosis Factor-alpha; D000077556:Alitretinoin; D014212:Tretinoin; D007633:Keratins; D013755:Tetradecanoylphorbol Acetate