DHEA metabolism in arthritis - A role for the p450 enzyme Cyp7b at the immune-endocrine crossroad

John Dulos*, Annemieke H. Boots

*Bijbehorende auteur voor dit werk

Onderzoeksoutput: Conference contributionAcademic

14 Citaten (Scopus)

Samenvatting

For dehydroepiandrosterone (DUEA) 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 7 alpha-hydroxy-DHEA (7 alpha-OH-DHEA) by the activity of the p450 enzyme, Cyp7b. 7 alpha-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 7 alpha-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-1 beta (IL-1 beta) 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-1 beta) 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 (NF kappa B) and activator protein-1 (AP-1) in the regulation of Cyp7b expression. Finally, we established that the effects of DHEA or 7 alpha-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.

Originele taal-2English
TitelBASIC AND CLINICAL ASPECTS OF NEUROENDOCRINE IMMUNOLOGY IN RHEUMATIC DISEASES
RedacteurenM Cutolo
Plaats van productieOXFORD
UitgeverijBlackwell Publishing
Pagina's401-413
Aantal pagina's13
ISBN van geprinte versie1-57331-593-1
DOI's
StatusPublished - 2006
Evenement3rd International Conference on Neuroendocrine Immune Basis of the Rheumatic Diseases - Genova, Italy
Duur: 10-sep-200512-sep-2005

Publicatie series

NaamANNALS OF THE NEW YORK ACADEMY OF SCIENCES
UitgeverijBLACKWELL PUBLISHING
Volume1069
ISSN van geprinte versie0077-8923

Conference

Conference3rd International Conference on Neuroendocrine Immune Basis of the Rheumatic Diseases
Land/RegioItaly
Periode10/09/200512/09/2005

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