Acute inflammation plays an important role in the normal immune system by helping to coordinate host responses to danger signals such as infection. In most cases the inflammation is rapidly resolved but in chronic inflammatory diseases such as rheumatoid arthritis (RA) the inflammation persists leading to localized accumulation of potentially damaging immune cells. 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 directing local immune responses and disease persistence. We have hypothesized that activation of glucocorticoids (GCs) via the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an important facet of stromal cell function acting as an autocrine anti-inflammatory pathway. To test this hypothesis we have assessed changes in 11beta-HSD1) expression and activity in fibroblasts isolated from different tissue sites (epidermis, bone marrow, synovium) in 5 subjects. Cells were cultured in the presence or absence of an inflammatory stimulus (TNFalpha, 10ng/ml, 24 hrs) and expression of target genes assessed by quantitative RT-PCR. The glucocorticoid receptor isoforms alpha and beta were expressed to a similar degree in all tissues and showed no significant change in expression following treatment with TNFalpha. However, expression of 11beta-HSD1 was dramatically increased in dermal (23-fold), bone marrow (15-fold) and synovial (8-fold). However, baseline and TNFalpha-induced expression of 11beta-HSD1 was significantly higher in synovial fibroblasts compared to other types of fibroblasts. Enzyme activity assays confirmed that TNFalpha induction of 11beta-HSD1 in fibroblasts was accompanied by increased capacity for cortisol generation. We postulate that tissue-specific variations in the autocrine activation of GCs via 11beta-HSD1 may play an important role in defining the impact of stromal cells on the persistence of inflammatory disease.
04 - 06 Apr 2005
British Endocrine Societies