Steroid synthesis by primary human keratinocytes; implications for skin disease

Hannen, Rosalind; Michael, Anthony E.; Jaulim, Adil; Bhogal, Ranjit; Burrin, Jacky M.; Philpott, Michael P.

doi:10.1016/j.bbrc.2010.11.059

Cited by 84 publications

(92 citation statements)

References 20 publications

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“…Although our studies were conducted in mice, the ability of human skin to synthesize cortisol de novo also remains debatable, with studies reporting both negative (Slominski et al 2002) and positive findings (Cirillo & Prime 2011, Hannen et al 2011, Vukelic et al 2011. Moreover, the quantities of cortisol generated de novo in these studies appear to be considerably lower than those reported to be generated by 11b-HSD1 in human skin (Tiganescu et al 2011(Tiganescu et al , 2013.…”

Section: Discussionmentioning

confidence: 77%

“…It is important to emphasize that differences in skin endocrine pathways do exist between mice and man, including for CRH and proopiomelanocortin (Slominski et al 2000b) in addition to 11b-HSD2 and CYP11B1 which are expressed in human skin (Brown et al 1996, Hannen et al 2011. Although our studies were conducted in mice, the ability of human skin to synthesize cortisol de novo also remains debatable, with studies reporting both negative (Slominski et al 2002) and positive findings (Cirillo & Prime 2011, Hannen et al 2011, Vukelic et al 2011.…”

Section: Discussionmentioning

confidence: 92%

“…Expression of steroidogenic enzymes in this pathway, including cytochromes CYP11A1, CYP17A1, and CYP21A2 has been detected in human skin (Slominski et al 1996), with cortisol synthesis detected in hair follicles (Ito et al 2005), keratinocytes (Cirillo & Prime 2011, Hannen et al 2011, Vukelic et al 2011, melanocytes (Slominski et al 2005a), and fibroblasts (Slominski et al 2005b(Slominski et al , 2006. Corticosterone synthesis has also been detected in rodent skin (Slominski et al 2000a).…”

Section: Introductionmentioning

confidence: 99%

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Increased glucocorticoid activation during mouse skin wound healing

Tiganescu

Hupe

Uchida

et al. 2014

Journal of Endocrinology

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Glucocorticoid (GC) excess inhibits wound healing causing increased patient discomfort and infection risk. 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) activates GCs (converting 11-dehydrocorticosterone to corticosterone in rodents) in many tissues including skin, where de novo steroidogenesis from cholesterol has also been reported. To examine the regulation of 11b-HSD1 and steroidogenic enzyme expression during wound healing, 5 mm wounds were generated in female SKH1 mice and compared at days 0, 2, 4, 8, 14, and 21 relative to unwounded skin. 11b-HSD1 expression (mRNA and protein) and enzyme activity were elevated at 2 and 4 days post-wounding, with 11b-HSD1 localizing to infiltrating inflammatory cells. 11b-HSD2 (GC-deactivating) mRNA expression and activity were undetectable. Although several steroidogenic enzymes displayed variable expression during healing, expression of the final enzyme required for the conversion of 11-deoxycorticosterone to corticosterone, 11b-hydroxylase (CYP11B1), was lacking in unwounded skin and post-wounding. Consequently, 11-deoxycorticosterone was the principal progesterone metabolite in mouse skin before and after wounding. Our findings demonstrate that 11b-HSD1 activates considerably more corticosterone than is generated de novo from progesterone in mouse skin and drives GC exposure during healing, demonstrating the basis for 11b-HSD1 inhibitors to accelerate wound repair.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Increased glucocorticoid activation during mouse skin wound healing

Tiganescu

Hupe

Uchida

et al. 2014

Journal of Endocrinology

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“…They showed that normal epidermis and cultured PHK express each of the enzymes (CYP11A1, CYP17A1, 3 HSD1, CYP21 and CYP11B1) that are required for cortisol synthesis. Collectively these data show that PHK are capable of extraadrenal cortisol synthesis, which could be a fundamental pathway in skin biology with implications in psoriasis and atopic dermatitis (Hannen et al, 2011).…”

Section: Psoriasis and Steroidogenic Capabilities Of Keratinocytesmentioning

confidence: 76%

“…Evers ' s study in 2010 is the first longitudinal study of patients with psoriasis to show a relationship between cortisol levels and daily stressors, these results suggest that patients who continuously experience higher levels of daily stressors are characterized by persistently lower cortisol levels and might thus be more vulnerable to the effects of stress on their disease (Everse et al, 2010). Hannen et al, in 2011 demonstrated that primary human Keratinocytes (PHK) express all the elements required for cortisol steroidogenesis and metabolite pregnenolone through each intermediate steroid to cortisol. They showed that normal epidermis and cultured PHK express each of the enzymes (CYP11A1, CYP17A1, 3 HSD1, CYP21 and CYP11B1) that are required for cortisol synthesis.…”

Section: Psoriasis and Steroidogenic Capabilities Of Keratinocytesmentioning

confidence: 99%

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology

Zangeneh¹,

Fazeli²,

Shooshtary³

2012

Psoriasis

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Keratinocytes synthesize and activate cortisol

Cirillo¹,

Prime²

2011

J. Cell. Biochem.

104

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The bioavailability of circulating and/or endogenous hydrocortisone (cortisol) in epidermal cells is a key determinant in inflammatory disease and chronic wounds. It is not known, however, whether epidermal cells can regulate tissue cortisol and whether they are capable of producing endogenous glucocorticoids. In the present study, we show by microarray analysis that epidermal cells express mRNAs to all the major enzymes involved in the metabolic chain from cholesterol to cortisol, including cytocrome P450 chain, 11β-hydroxysteroid dehydrogenases (HSD11Bs), adrenocorticotropic hormone (ACTH) receptor (MC2R), and glucocorticoid receptor. The two enzymes mediating activation/deactivation of cortisone to cortisol, namely HSD11B1 and HSD11B2, were expressed at the protein level in cultured keratinocytes as well as human skin samples, as shown by Western blotting and immunohistochemistry, respectively. In functional assays, we show that keratinocytes are not only able to activate cortisone to cortisol in a HSD11B-dependent manner but also silencing of either HSD11B1 or HSD11B2 specifically modulates the bioavailability of the inactive glucocorticoid and the active steroid, respectively. A further key observation was that keratinocytes responded to stimulation with ACTH by a significant increase in the de novo synthesis of cortisol. Taken together, we provide evidence for a novel non-adrenal steroideal system in human keratinocytes.

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Steroid synthesis by primary human keratinocytes; implications for skin disease

Cited by 84 publications

References 20 publications

Increased glucocorticoid activation during mouse skin wound healing

Increased glucocorticoid activation during mouse skin wound healing

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology

Keratinocytes synthesize and activate cortisol

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