Effects of Cellular 11β-hydroxysteroid Dehydrogenase 1 on LPS-induced Inflammatory Responses in Synovial Cell Line, SW982

Abstract

11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyzes the conversion of inactive cortisone into active cortisol, which has pleiotropic roles in various biological conditions, such as immunological and metabolic homeostasis. Cortisol is mainly produced in the adrenal gland, but can be locally regenerated in the liver, fat, and muscle. Its diverse actions are primarily mediated by binding to the glucocorticoid receptor. SW982, a human synovial cell line, expresses 11β-HSD type 1, but not type 2, that catalyzes the conversion of cortisone to cortisol. In this study, therefore, we investigated the control of lipopolysaccharide (LPS)-induced inflammatory responses by prereceptor regulation-mediated maintenance of cortisol levels. Preliminarily, cell seeding density and incubation period were optimized for analyzing the catalytic activity of SW982. Additionally, cellular 11β-HSD1 still remained active irrespective of monolayer or spheroid culture conditions. Inflammatory stimulants, such as interleukin (IL)-1β, tumor necrosis factor (TNF)α, and LPS, did not affect the catalytic activity of 11β-HSD1, although a high dose of LPS significantly decreased its activity. Additionally, autocrine effects of cortisol on inflammatory responses were investigated in LPS-stimulated SW982 cells. LPS upregulated pro-inflammatory cytokines, including IL-6 and IL-1β, in SW982 cells, while cortisol production, catalyzed by cellular 11β-HSD1, downregulated LPS-stimulated cytokines. Furthermore, suppression of NFκB activation-mediated pro-inflammatory responses by cortisol was revealed. In conclusion, the activity of cellular 11β-HSD1 was closely correlated with suppression of LPS-induced inflammation. Therefore, these results partly support the notion that prereceptor regulation of locally regenerated cortisol could be taken into consideration for treatment of inflammation-associated diseases, including arthritis.