Local Glucocorticoid Activation by 11β-Hydroxysteroid Dehydrogenase 1 in Keratinocytes

Abstract

Over the past decade, extra-adrenal cortisol production was reported in various tissues. The enzyme that catalyzes the conversion of hormonally inactive cortisone into active cortisol in cells is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is also expressed in keratinocytes and regulates inflammation and keratinocyte proliferation. To investigate the function of 11β-HSD1 in keratinocytes during inflammation in vivo, we created keratinocyte-specific 11β-HSD1 knockout (K5-Hsd11b1-KO) mice and analyzed the inflammatory response in models of hapten-induced contact irritant dermatitis. K5-Hsd11b1-KO mice showed enhanced ear swelling in low-dose oxazolone-, 2,4,6-trinitro-1-chlorobenzene (TNCB)-, and 2,4-dinitrofluorobenzene-induced irritant dermatitis associated with increased inflammatory cell infiltration. Topical application of corticosterone dose dependently suppressed TNCB-induced ear swelling and cytokine expression. Similarly in mouse keratinocytes in vitro, corticosterone dose dependently suppressed 2,4,6-trinitrobenzenesulfonic acid-induced IL-1α and IL-1β expression. The effect of 11-dehydrocorticosterone was attenuated in TNCB-induced irritant dermatitis in K5-Hsd11b1-KO mice compared with wild-type mice. In human samples, 11β-HSD1 expression was decreased in epidermis of psoriasis vulgaris compared with healthy skin. Taken together, these data suggest that corticosterone activation by 11β-HSD1 in keratinocytes suppresses hapten-induced irritant dermatitis through suppression of expression of cytokines, such as IL-1α and IL-1β, in keratinocytes.

Endogenous Glucocorticoid Deficiency in Psoriasis Promotes Inflammation and Abnormal Differentiation

“…In contrast, silencing of HSD11B2 leads to elevation of cortisol levels (Cirillo and Prime, 2011) demonstrating that the relative levels and activities of these two enzymes determine the overall levels of glucocorticoids locally present in the skin (Cirillo and Prime, 2011; Tiganescu et al , 2011). In psoriatic skin, the mRNA expression of both HSD11B1 , consistent with findings from a recent study (Terao et al , 2016), and HSD11B2 is decreased, but the ratio between these two enzymes is biased toward greater suppression of HSD11B1 and therefore less production of cortisol. This is similar to what we observe in several other skin diseases and wound healing (Supplementary file 4).…”

Attenuated Activation of Homeostatic Glucocorticoid in Keratinocytes Induces Alloknesis via Aberrant Artemin Production

“…GC, glucocorticoid; NHEK, normal human keratinocyte; RT-qPCR, quantitative real-time PCR; WT, wild type. local stress regulatory system is disrupted in Hsd11b1 KCe/e epidermis (Terao et al, 2016). Therefore, we hypothesized that disruption of the local stress regulatory system in skin could contribute to alloknesis as part of a compensatory hostdefense mechanism.…”

“…Keratinocyte-specific Hsd11b1 KCe/e mice were generated as described previously (Terao et al, 2016). Briefly, Krt5-Cre þ/þ transgenic and Hsd11b1 flox/flox mice were maintained on a C57BL6/J background and interbred to generate mice that carried Krt5-Cre transgene and a floxed Hsd11b1 allele (Krt5-Cre þ/e Hsd11b1 flox/e ).…”

“…In normal skin tissue, HSD11b1 is expressed in keratinocytes, fibroblasts, and melanocytes (Skobowiat et al, 2013;Terao et al, 2011;Tiganescu et al, 2011). Endogenous GCs activated by HSD11b1 in keratinocytes are thought to maintain skin homeostasis by regulating epidermal differentiation and local inflammation induced by environmental stimuli, such as UVB radiation, burning, hapten exposure, and dry conditions (Skobowiat et al, 2013;Takei et al, 2013;Terao et al, 2016;Vukelic et al, 2011). Therefore, we hypothesized that an endogenous GC deficiency might negatively affect itch symptoms induced by environmental stimulus.…”

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.…”