11β-Hydroxysteroid dehydrogenase type 1 amplifies inflammation in LPS-induced THP-1 cells

Objective(s): The role of glucocorticoids as anti-inflammatory and immune-stimulatory drugs has been widely reported. However, the role of 11B-hydroxysteroid dehydrogenase type 1 (11B-HSD1), which catalyzes the conversion of inactive cortisone into active cortisol, in inflammation remains unclear. This study aimed to examine the mechanism of actions of 11B-HSD1 in lipopolysaccharide (LPS)-induced THP-1 cells. Materials and Methods: The gene expression of 11B-HSD1 and pro-inflammatory cytokines was detected via RT-PCR. The protein expression of IL-1B in cell supernatants was detected via ELISA. Oxidative stress and mitochondrial membrane potential were assessed using a reactive oxygen species (ROS) kit and a mitochondrial membrane potential (MMP) kit, respectively. The expression of Nuclear Factor-Kappa B (NF -KB) and mitogen-activated protein kinase (MAPK) was detected via western blotting.Results: Elevated levels of 11B-HSD1 contributed to the expression of inflammatory cytokines, whereas BVT.2733, a selective 11B-HSD1 inhibitor, ameliorated inflammatory responses, ROS, and mitochondrial damage in LPS-stimulated THP-1 cells. Furthermore, cortisone and cortisol, which are the substrate and product of 11B-HSD1, respectively, showed biphasic responses and induced the expression of pro-inflammatory cytokines at a low concentration in both LPS-stimulated or untreated THP-1 cells. The enhanced inflammation was attenuated by co-treatment with BVT.2733 and the glucocorticoid receptor (GR) antagonist RU486, but not in those treated with the mineralocorticoid receptor (MR) antagonist spironolactone. Overall, the results indicate that 11B-HSD1 amplifies inflammatory responses by activating the NF-KB and MAPK signaling pathways.Conclusion: Inhibition of 11B-HSD1 may serve as a potential therapeutic target against the excessive activation of inflammation.