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 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1). We recently reported that 11 beta-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11 beta-HSD1 in skin inflammation. Expression of 11 beta-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1 beta and TNF alpha. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11 beta-HSD1 in response to pro-inflammatory cytokines, we knocked down 11 beta-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1 beta or TNF alpha stimulation was attenuated in NHEKs transfected with si11 beta-HSD1 compared with control cells. In addition, IL-1 beta-induced IL-6 production was enhanced in cultures containing 1 x 10(-13) M cortisol, whereas 1 x 10(-5) M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11 beta-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations by 11 beta-HSD1 appears to modulate expression of inflammatory cytokines in NHEKs. (C) 2013 Elsevier Inc. All rights reserved.