TY - JOUR
T1 - Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids
T2 - implications for inflammation associated bone loss
AU - Kaur, K.
AU - Hardy, R.
AU - Ahasan, M. M.
AU - Eijken, M.
AU - van Leeuwen, J. P.
AU - Filer, A.
AU - Thomas, A. M.
AU - Raza, K.
AU - Buckley, C. D.
AU - Stewart, P. M.
AU - Rabbitt, E. H.
AU - Hewison, M.
AU - Cooper, M. S.
PY - 2010/6
Y1 - 2010/6
N2 - Objectives Synovial fibroblasts and osteoblasts generate active glucocorticoids by means of the 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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-1 beta/tumour necrosis factor alpha; TNF alpha) and glucocorticoids, alone or combined, were assessed on the expression and activity of 11 beta-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 11 beta-HSD1 expression and activity. However, in combination, 11 beta-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 11 beta-HSD1 gene. Synergistic induction had functional consequences on IL-6 production.Conclusions Combined treatment with inflammatory cytokines and glucocorticoids synergistically induces 11 beta-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 11 beta-HSD1 might also cause detrimental glucocorticoid accumulation in bone or surrounding tissues.
AB - Objectives Synovial fibroblasts and osteoblasts generate active glucocorticoids by means of the 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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-1 beta/tumour necrosis factor alpha; TNF alpha) and glucocorticoids, alone or combined, were assessed on the expression and activity of 11 beta-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 11 beta-HSD1 expression and activity. However, in combination, 11 beta-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 11 beta-HSD1 gene. Synergistic induction had functional consequences on IL-6 production.Conclusions Combined treatment with inflammatory cytokines and glucocorticoids synergistically induces 11 beta-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 11 beta-HSD1 might also cause detrimental glucocorticoid accumulation in bone or surrounding tissues.
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=eur_pure&SrcAuth=WosAPI&KeyUT=WOS:000278017700045&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1136/ard.2009.107466
DO - 10.1136/ard.2009.107466
M3 - Article
C2 - 19549618
SN - 0003-4967
VL - 69
SP - 1185
EP - 1190
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
IS - 6
ER -