Tissue inflammation is usually transient but in diseases such as rheumatoid arthritis (RA) inflammation persists. It remains unclear why inflammation persists in some tissues and not in others. Recent studies have shown that stromal cells such as fibroblasts play a pivotal role in determining this persisitance. We have hypothesized that glucocorticoid (GC) activation via the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) within fibroblasts plays a key role in modulating inflammatory responses. 11beta-HSD1 converts inactive GCs (cortisone/prednisone) to their active counterparts (cortisol/prednisolone). 11beta-HSD1 expression varies between fibroblasts from different tissues with activity and expression higher in synovial fibroblasts than fibroblasts from bone marrow or skin. We have now tested the functional consequences of these expression differences on fibroblast production of IL-6. IL-6 mRNA expression and protein levels were measured in primary fibroblasts isolated from dermis (DM), bone marrow (BM), and synovium (SY) in 3 subjects with RA. Cells were cultured in the presence or absence of GC and gene expression assessed by quantitative RT-PCR. IL-6 generation was measured by ELISA. Treatment with 100nM cortisol decreased IL-6 mRNA expression in all fibroblasts (7-fold decrease with SY, 3.5-fold BM, 4.5-fold DM; all P<0.01). By contrast 100 nM cortisone decreased expression only in SY fibroblasts (5-fold) with no change in BM or DM fibroblasts. IL-6 ELISA assays displayed an identical pattern of expression with suppression by cortisol in all cells but cortisone only suppressing IL-6 generation in SY fibroblasts. The effects of cortisone, but not cortisol, were prevented by the 11beta-HSD1 inhibitor glycyrrhetinic acid. Local GC activation can decrease expression of IL-6, which in turn is likely to impact on leukocyte behaviour within the stromal environment. GC metabolism in synovial fibroblasts may be key to understanding the development of persistant inflammation in RA.
01 - 05 Apr 2006
European Society of Endocrinology