Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids: Implications for inflammation associated bone loss
Objectives: Synovial fibroblasts and osteoblasts generate active glucocorticoids by means of the 11aβ-hydroxysteroid dehydrogenase type 1 (11aβ-HSD1) enzyme. This activity increases in response to proinflammatory cytokines or glucocorticoids. During inflammatory arthritis synovium and bone are exposed to both these factors. This study hypothesised that glucocorticoids magnify the effects of inflammatory cytokines on local glucocorticoid production in both synovium and bone. Methods: The effects of inflammatory cytokines (IL-1aβ/tumour necrosis factor alpha; TNFα) and glucocorticoids, alone or combined, were assessed on the expression and activity of 11β-HSD1 in primary synovial fibroblasts, primary human osteoblasts and MG-63 osteosarcoma cells. A range of other target genes and cell types were used to examine the specificity of effects. Functional consequences were assessed using IL-6 ELISA. Results: In synovial fibroblasts and osteoblasts, treatment with cytokines or glucocorticoids in isolation induced 11β-HSD1 expression and activity. However, in combination, 11β-HSD1 expression, activity and functional consequences were induced synergistically to a level not seen with isolated treatments. This effect was seen in normal skin fibroblasts but not foreskin fibroblasts or adipocytes and was only seen for the 11β-HSD1 gene. Synergistic induction had functional consequences on IL-6 production. Conclusions: Combined treatment with inflammatory cytokines and glucocorticoids synergistically induces 11aβ-HSD1 expression and activity in synovial fibroblasts and osteoblasts, providing a mechanism by which synovium and bone can interact to enhance anti-inflammatory responses by increasing localised glucocorticoid levels. However, the synergistic induction of 11β-HSD1 might also cause detrimental glucocorticoid accumulation in bone or surrounding tissues.
|Keywords||11beta hydroxysteroid dehydrogenase 1, article, bone, cancer cell, cell type, controlled study, cytokine, disease association, enzyme linked immunosorbent assay, fibroblast, gene targeting, glucocorticoid, human, human cell, human tissue, hypothesis, interleukin 1beta, interleukin 6, osteoblast, osteolysis, osteosarcoma cell, priority journal, protein expression, rheumatoid arthritis, synovium, tumor necrosis factor alpha|
|Persistent URL||dx.doi.org/10.1136/ard.2009.107466, hdl.handle.net/1765/20327|
|Journal||Annals of the Rheumatic Diseases: an international peer-reviewed journal for health professionals and researchers in the rheumatic diseases|
Kaur, K, Hardy, R, Ahasan, M.M, Eijken, H.J.M, van Leeuwen, J.P.T.M, Filer, A, … Cooper, M.S. (2010). Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids: Implications for inflammation associated bone loss. Annals of the Rheumatic Diseases: an international peer-reviewed journal for health professionals and researchers in the rheumatic diseases, 69(6), 1185–1190. doi:10.1136/ard.2009.107466