PT  - JOURNAL ARTICLE
AU  - K Kaur
AU  - R Hardy
AU  - M M Ahasan
AU  - M Eijken
AU  - J P van Leeuwen
AU  - A Filer
AU  - A M Thomas
AU  - K Raza
AU  - C D Buckley
AU  - P M Stewart
AU  - E H Rabbitt
AU  - M Hewison
AU  - M S Cooper
TI  - Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids: implications for inflammation associated bone loss
AID  - 10.1136/ard.2009.107466
DP  - 2010 Jun 01
TA  - Annals of the Rheumatic Diseases
PG  - 1185--1190
VI  - 69
IP  - 6
4099  - http://ard.bmj.com/content/69/6/1185.short
4100  - http://ard.bmj.com/content/69/6/1185.full
SO  - Ann Rheum Dis2010 Jun 01; 69
AB  - Objectives Synovial fibroblasts and osteoblasts generate active glucocorticoids by means of the 11β-hydroxysteroid dehydrogenase type 1 (11β-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-1β/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 11β-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.