Local metabolism of glucocorticoids and its role in rat adjuvant arthritis

• Published in: Molecular and cellular endocrinology Vol. 323; no. 2; pp. 155 - 160
• Main Authors: Ergang, Peter, Leden, Pavel, Vagnerová, Karla, Klusoňová, Petra, Mikšík, Ivan, Jurčovičová, Jana, Kment, Milan, Pácha, Jiří
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 29.07.2010
• Subjects: 11-beta-Hydroxysteroid Dehydrogenases - genetics; 11-beta-Hydroxysteroid Dehydrogenases - metabolism; 11β-Hydroxysteroid dehydrogenase regulation; Adjuvants; Animals; Anti-Ulcer Agents - pharmacology; Arthritis; Arthritis, Experimental - genetics; Arthritis, Experimental - metabolism; Carbenoxolone - pharmacology; Cells, Cultured; Control systems; Control theory; Cytokines - metabolism; Feedback; Glucocorticoids; Glucocorticoids - metabolism; Hormone Antagonists - pharmacology; Humans; Inhibitors; Isoenzymes - genetics; Isoenzymes - metabolism; Lewis rats; Male; Metabolism; Mifepristone - pharmacology; Rats; Rats, Inbred Lew; RNA, Messenger - metabolism; Synovial Membrane - cytology; Synovial Membrane - drug effects; Synovial Membrane - metabolism; 11β-Hydroxysteroid dehydrogenase regulation; Arthritis; Lewis rats
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2010.03.003

11β-Hydroxysteroid dehydrogenase 1 (11HSD1) regulates local glucocorticoid activity and plays an important role in various diseases. Here, we studied whether arthritis modulates 11HSD1, what is the role of pro-inflammatory cytokines in this process and whether altered local metabolism of glucocorticoids may contribute to the feedback regulation of inflammation. Adjuvant arthritis increased synovial 11HSD1 mRNA and 11-reductase activity but treatments with tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) antagonists etanercept and anakinra reduced 11HSD1 upregulation. Treatment with carbenoxolone, an 11HSD inhibitor, increased expression of TNF-α, cyclooxygenase 2, and osteopontin mRNA without any changes in the plasma levels of corticosterone. Similar changes were observed when arthritic rats were treated with RU486, an antagonist of GR. This study suggests that arthritis upregulates synovial 11HSD1, this upregulation is controlled by TNF-α and IL-1β and that the increased supply of local corticosterone might contribute to feedback regulation of inflammation.