CYP7B Expression and Activity in Fibroblast-Like Synoviocytes From Patients With Rheumatoid Arthritis Regulation by Proinflammatory Cytokines

Objective. The cytochrome P450 enzyme CYP7B catalyzes the conversion of dehydroepiandrosterone (DHEA) into 7 alpha-hydroxy-DHEA (7 alpha-OH-DHEA). This metabolite can stimulate the immune response. We previously reported that the severity of murine collagen-induced arthritis is correlated with CYP7B messenger RNA (mRNA) expression and activity in the arthritic joint. The purpose of this study was to investigate the presence of 7 alpha-OH-DHEA in synovial samples and the cytokine regulation of CYP7B activity in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). Methods. The presence of 7 alpha-OH-DHEA was examined in synovial biopsy tissues, synovial fluid, and serum by radioimmunoassay. The effect of cytokines on CYP7B mRNA expression and CYP7B activity in FLS was examined by determining the formation of the CYP7B enzyme product 7 alpha-OH-DHEA with the use of high-performance liquid chromatography. Results. The CYP7B enzyme product 7 alpha-OH-DHEA was found in synovial biopsy tissues, synovial fluid, and serum from RA patients. The proinflammatory cytokines tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), IL-1 beta, and IL-17 up-regulated CYP7B activity in an FLS cell line 2-10-fold. Enhanced CYP7B activity was correlated with an increase in CYP7B mRNA. The cytokine transforming growth factor beta inhibited CYP7 beta activity. Moreover, CYP7B activity was detected in 10 of 13 unstimulated synovial fibroblast cell lines. Stimulation with TNF alpha increased CYP7 beta activity in all cell lines tested. Conclusion. Exposure to the proinflammatory cytokines TNF alpha, IL-1 alpha, IL-1,6, and IL-17 increases CVP7B activity in synovial tissue. Increased CYP7B activity leads to higher levels of the DHEA metabolite 7 alpha-OH-DHEA in synovial fluid, which may contribute to the maintenance of the chronic inflammation observed in RA patients.