DHEA metabolism in arthritis: a role for the p450 enzyme Cyp7b at the immune-endocrine crossroad.
For dehydroepiandrosterone (DHEA) both immunosuppressive and immuno-stimulating properties have been described. The immunosuppressive effects may be explained by the conversion of DHEA into androgens and/or estrogens. The described immuno-stimulating effects of DHEA may be due to the conversion of DHEA into 7alpha-hydroxy-DHEA (7alpha-OH-DHEA) by the activity of the p450 enzyme, Cyp7b. 7alpha-OH-DHEA is thought to have anti-glucocoticoid activity preventing the anti-inflammatory action of endogenous glucocorticoids. To investigate a putative role of Cyp7b in the arthritic process, tissues from both the murine collagen-induce arthritis (CIA) model and from patients with rheumatoid arthritis (RA) were studied. We determined the Cyp7b expression levels in synovial tissue and the level of 7alpha-OH-DHEA in both serum and arthritic joints of mice with CIA. Our studies showed that the severity of arthritis correlates with increased Cyp7b activity. Next, we investigated Cyp7b expression and activity in RA patients where the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are known to control the disease process. Fibroblast-like synoviocytes (FLS), isolated from RA synovial biopsies were found to express Cyp7b mRNA. In addition, Cyp7b enzymatic activity was detected in these cells. We also investigated whether Cyp7b activity is regulated by cytokines. Proinflammatory (e.g., TNF-alpha and IL-1beta) cytokines were found to stimulate Cyp7b activity and the anti-inflammatory cytokine transforming growth factor-beta (TGF-beta) was found to suppress Cyp7b activity in FLS. Next, we studied which signal transduction pathway is involved in the TNF-alpha-mediated induction of Cyp7b activity in human FLS. The results show a role for nuclear factor kappa B (NFkappaB) and activator protein-1 (AP-1) in the regulation of Cyp7b expression. Finally, we established that the effects of DHEA or 7alpha-OH-DHEA on the immune system can not be explained by glucocorticoid receptor (GR) engagement. The role of the p450 enzyme Cyp7b in DHEA metabolism and its relevance in the arthritic process will be discussed.
Dulos
John
J
Department of Pharmacology, Section Autoimmunity, Room RE3211, N.V. Organon, PO Box 20, 5340 BH Oss, The Netherlands. John.Dulos@Organon.com
Boots
Annemieke H
AH
D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000378:metabolism* / Q000494:pharmacology; D004703:Endocrine System / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D007596:Joints / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D005938:Glucocorticoids; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D003687:Dehydroepiandrosterone; D002790:Cholesterol 7-alpha-Hydroxylase