Interferon Gamma Induces Steroid Sulfatase Expression in Human Keratinocytes

Abstract

Key words steroid sulfatase; keratinocyte; interferon gamma; nuclear factor-kappa B; dexamethasone Steroid sulfatase (STS) is a microsomal enzyme that catalyzes the hydrolysis of sulfated 3-hydroxysteroids to the corresponding free active 3-hydroxysteroids.1) This enzyme is widely distributed throughout the body, and its actions are implicated in both physiological processes and pathological conditions. In many peripheral organs such as skin STS play a key role in the production of dehydroepiandrosterone (DHEA) from DHEA sulfate, which is abundant in the circulation. DHEA is then used as a major precursor for the synthesis of potent androgens in the skin.2) Early studies in vitro and in vivo have shown that the human STS activity appears in specific skin types, such as in foreskin and infantile abdominal skin, after birth.3) It also has been shown that STS plays an important functional role in the skin as this enzyme is deficient in X-linked ichthyosis (X-LI). 4,5) It has been further demonstrated that both the expression of STS mRNA and its enzymatic activity are increased in malignant breast and endometrial tissues compared with nonmalignant tissues and that this increased STS affects active estrogen levels within cells by hydrolysis of inactive estrogen sulfates. 6) We recently reported that estradiol sulfate, whose formation is catalyzed by estrogen sulfotransferase, is a major metabolite of estradiol in human epidermal keratinocytes. 7) Since estrogens have a significant effect on skin differentiation and development, 8,9) the activity of STS, as well as of estrogen sulfotransferase in the skin must be properly regulated to maintain cutaneous homeostasis. However, little is known about the regulation of STS gene expression or activity in skin.It has been reported previously that interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) act synergistically to increase STS activity in breast cancer cells, 10,11) and that this effect on STS activity is regulated by posttranslational modification of a cysteine residue in the catalytically active site of this enzyme to formyl glycine. In contrast, the inflammatory cytokine IL-1β decreases STS activity and the expression of STS mRNA in human endometrial stromal cells.12) In psoriatic plaques in skin, there is a predominance of T helper 1 cytokines, most notably interferon gamma (IFNγ).13) IFNγ is a cytokine that is produced by activated T cells and natural killer cells, and induces a variety of effects including anti-viral responses, cell growth and differentiation. 14) In the skin, IFNγ is known to play a pivotal role in the development of inflammatory and immune responses. [15][16][17] However, no information is available concerning the effect of IFNγ on STS expression. IFNγ has been reported to stimulate involucrin gene expression via STAT1 signaling in cells of the SVHK cell line that was established from SV40-transformed human keratinocytes. 18,19) To determine the effect of IFNγ on STS expression in the human epidermis, we investigated the effects of IFNγ...

Role of cholesterol sulfate in epidermal structure and function: Lessons from X-linked ichthyosis

“…It is located proximal to the portion of the gene that encodes enzyme expression, but the promoter sequence varies in a tissue-specific fashion [54]. While cytokines such as TNFα and IL-6 upregulate enzyme activity, IL-1β instead reportedly downregulates SSase activity [55], although IL-1β (as well as interferon γ) reportedly down-regulate SSase expression by inhibiting NFkB, while activating the glucocorticoidreceptor [55]. Finally, both retinoids and 1,25(OH) 2 vitamin D3 induce both SSase activity and expression [56].…”

Glucocorticoid insensitivity by staphylococcal enterotoxin B in keratinocytes of allergic dermatitis is associated with impaired nuclear translocation of the Glucocorticoid Receptor α

“…These properties, as well as the relative long life of a keratinocyte compared with other inflammatory cells such as the neutrophil or eosinophil, make the keratinocyte a potentially important player in the amplification and persistence of inflammatory and immune responses in AD. Several groups have reported that GC exhibits anti-inflammatory eff ;ects in keratinocytes treated with TNFα [32,33], hapten [34], UV-B irradiation [35], IFNg [36], and induces keratinocyte terminal differentiation [37]. However, few investigations have been conducted to determine whether SEB contributes to the resistance to GCs through keratinocytes.…”

Detection of a novel, primate-specific ‘kill switch’ tumor suppression mechanism that may fundamentally control cancer risk in humans: an unexpected twist in the basic biology of TP53

“…G6PD E:S then acts as a sink for DHEA, stimulating OATP2B1, the transport protein responsible for importing DHEAS into the cell. Inactivation of TP53 also hyperactivates NFKB ( Weisz et al 2007 , Kawauchi et al 2008 , Cooks et al 2013 ), triggering steroid sulfatase ( Hattori et al 2012 , Dias & Selcer 2016 ), which potentiates the importation of DHEAS and its intracellular activation to DHEA. OATP2B1 is also stimulated by the intracellular presence of de-sulfated androgens ( Grube et al 2006 ), such that as the intracellular concentration of DHEA rises, DHEAS is imported into the p53-affected cell at an ever-accelerating rate.…”