alitretinoin and Hypothyroidism

Topics: Adult; Aged; Alitretinoin; Female; Humans; Hypothyroidism; Ichthyosis, Lamellar; Keratin-10; Keratolytic Agents; Male; Middle Aged; Mutation; Pilot Projects; Transglutaminases; Tretinoin

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.. 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.. 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.

Topics: Alitretinoin; Animals; Blotting, Western; Cell Differentiation; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Epidermis; Female; Hyperplasia; Hypothyroidism; Interleukin-6; Keratins; Lymphocytes; Macrophages; Male; Mice; Mice, Knockout; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; Skin; Tetradecanoylphorbol Acetate; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Tretinoin; Tumor Necrosis Factor-alpha

The prohormone convertases (PCs) PC1 and PC2 are key enzymes capable of processing a variety of prohormones to their bioactive forms. In this study, we demonstrated that 6-n-propyl-2-thiouracil (PTU)-induced hypothyroidism stimulated, whereas triido-L-thyronine (T(3))-induced hyperthyroidism suppressed, PC1 mRNA levels in the rat anterior pituitary. Using 5' deletions of the human PC1 (hPC1) promoter transiently transfected into GH3 (a somatotroph cell line) cells, we found that T(3) negatively regulated hPC1 promoter activity and that this regulation required the region from -82 to +19 bp relative to the transcription start site. Electrophoretic mobility shift assays (EMSAs) using purified thyroid hormone receptor-alpha1 (TR alpha 1) and retinoid X receptor-beta (RXRbeta) proteins and GH3 nuclear extracts demonstrated that the region from -10 to +19 bp of the hPC1 promoter bound TR alpha 1 as both a monomer and a homodimer and bound TR alpha 1/RXR beta as a heterodimer and multimer. EMSAs with oligonucleotides containing point mutations of the putative negative thyroid response elements (TREs) exhibited diminished homodimer and loss of multimer binding. We conclude that there are multiple novel TRE-like sequences in the hPC1 promoter located from -10 to +19 bp.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Aspartic Acid Endopeptidases; Cells, Cultured; Gene Deletion; Gene Expression Regulation, Enzymologic; Genes, Reporter; Hypothyroidism; Luciferases; Male; Mutagenesis, Insertional; Oligonucleotides; Peptide Fragments; Pituitary Gland, Anterior; Promoter Regions, Genetic; Proprotein Convertases; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Retinoid X Receptors; RNA, Messenger; Transcription Factors; Tretinoin; Triiodothyronine; Uracil