11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes.
The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10(-13) M cortisol, whereas 1 × 10(-5) M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations by 11β-HSD1 appears to modulate expression of inflammatory cytokines in NHEKs.
Department of Dermatology, Integrated Medicine, Osaka University Graduate School of Medicine, Japan.
Saori
S
Itoi
Mika
M
Terao
Hiroyuki
H
Murota
Ichiro
I
Katayama
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D015603:Keratinocytes / Q000502:physiology* / Q000528:radiation effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014466:Ultraviolet Rays
D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone
11β-HSD1; 11β-Hydroxysteroid dehydrogenase 1; 11β-hydroxysteroid dehydrogenase 1; 2,4,6-trinitrobenzene sulfonic acid; Cortisol; GAPDH; GC; HPA; IL-6; IL-8; Inflammation; Keratinocyte; NHEKs; SD; TNBS; cDNA; complementary DNA; glucocorticoid; glyceraldehyde-3-phosphate dehydrogenase; hypothalamic–pituitary–adrenal; interleukin-6; interleukin-8; normal human epidermal keratinocytes; real-time polymerase chain reaction; rtPCR; standard deviation