title: Steroid synthesis by primary human keratinocytes; implications for skin disease.
abstract: Cortisol-based therapy is one of the most potent anti-inflammatory treatments available for skin conditions including psoriasis and atopic dermatitis. Previous studies have investigated the steroidogenic capabilities of keratinocytes, though none have demonstrated that these skin cells, which form up to 90% of the epidermis are able to synthesise cortisol. Here we demonstrate that primary human keratinocytes (PHK) express all the elements required for cortisol steroidogenesis and metabolise pregnenolone through each intermediate steroid to cortisol. We show that normal epidermis and cultured PHK express each of the enzymes (CYP11A1, CYP17A1, 3βHSD1, CYP21 and CYP11B1) that are required for cortisol synthesis. These enzymes were shown to be metabolically active for cortisol synthesis since radiometric conversion assays traced the metabolism of [7-(3)H]-pregnenolone through each steroid intermediate to [7-(3)H]-cortisol in cultured PHK. Trilostane (a 3βHSD1 inhibitor) and ketoconazole (a CYP17A1 inhibitor) blocked the metabolism of both pregnenolone and progesterone. Finally, we show that normal skin expresses two cholesterol transporters, steroidogenic acute regulatory protein (StAR), regarded as the rate-determining protein for steroid synthesis, and metastatic lymph node 64 (MLN64) whose function has been linked to cholesterol transport in steroidogenesis. The expression of StAR and MLN64 was aberrant in two skin disorders, psoriasis and atopic dermatitis, that are commonly treated with cortisol, suggesting dysregulation of epidermal steroid synthesis in these patients. Collectively these data show that PHK are capable of extra-adrenal cortisol synthesis, which could be a fundamental pathway in skin biology with implications in psoriasis and atopic dermatitis.
authors.affiliation: Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. r.f.hannen@qmul.ac.uk
authors.forename: Rosalind F
authors.initials: RF
authors.lastname: Hannen
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Michael
authors.forename: Adil
authors.initials: A
authors.lastname: Jaulim
authors.forename: Ranjit
authors.initials: R
authors.lastname: Bhogal
authors.forename: Jacky M
authors.initials: JM
authors.lastname: Burrin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Philpott
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000201:enzymology*; D004817:Epidermis / Q000201:enzymology*; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis*; D015603:Keratinocytes / Q000201:enzymology*; D011284:Pregnenolone / Q000378:metabolism; D011565:Psoriasis / Q000201:enzymology*; D013250:Steroid Hydroxylases / Q000378:metabolism*
chemical_list: D011284:Pregnenolone; D015096:3-Hydroxysteroid Dehydrogenases; D013250:Steroid Hydroxylases; D006854:Hydrocortisone