Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids: implications for inflammation associated bone loss

Abstract

ObjectivesSynovial 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.MethodsThe 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.ResultsIn 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.ConclusionsCombined 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.

11β-Hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation

“…1). These observations are in line with numerous reports on induction of HSD11B1 expression by the pro-inflammatory cytokines TNF-␣ and IL-1␤ in various cell types and lines including fibroblasts, adipocytes, osteoblasts and smooth muscle cells [12][13][14][77][78][79][80][81][82][83][84][85] ( Table 2).…”

Comparison of Osteogenic Differentiation of Embryonic Stem Cells and Primary Osteoblasts Revealed by Responses to IL-1β, TNF-α, and IFN-γ

“…Previous reports have focused on the effects of individual cytokines on osteoblast differentiation; but when used in combination, the effects are synergistic and enhanced [57,58]. IL-1b, TNF-a, and IFN-g have been shown to inhibit bone nodule formation, decrease ALP activity, inhibit OCN and col-I deposition, in both mouse and human osteoblasts [33,35,[59][60][61][62][63][64][65][66].…”

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

“…However, 11␤-HSD1 expression is synergistically induced by TNF-␣ or IL-1 and glucocorticoids in a range of cell types (338,403,567,681). The purpose might be to amplify intracellular glucocorticoid-mediated attenuation of proinflammatory cytokine action in preparation for recovery in key tissues.…”