Local glucocorticoids generation in the inflamed joint: regulation and functional consequences

[摘要] Inflammatory arthritis is common. In some patients it progresses to rheumatoid arthritis (RA) whilst in other it spontaneously resolves. There is a particular interest in endogenous anti-inflammatory mechanisms that might be implicated in disease resolution. Amongst these is the role of endogenously produced glucocorticoids (GCs) and in particular 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme that converts biologically inactive GCs such as cortisone into its active counterpart cortisol. This thesis assessed how the 11β-HSD1 enzyme is regulated in patients with inflammatory arthritis, in normal and RA synovial tissue / fluid, and what the functional consequences of expression were. I observed that 11β-HSD1 enzyme is expressed in different populations of fibroblasts and CD68 positive macrophages present in both lining and sub-lining layer of RA synovium. Subsequently, I showed that synovial fibroblasts were able to activate GCs and that this was enhanced by pro-inflammatory cytokines. I also demonstrated that synovial fluid neutrophils isolated from patients with RA express mRNA for 11β-HSD1 enzyme and may therefore represent an important site of local GCs metabolism. I demonstrated that there is an increase in the global measure of 11β-HSD1 activity in patients with active established RA and psoriatic arthritis and that this is inhibited by anti-TNFα therapy. I have also shown that patients with a new onset of synovitis whose disease subsequently resolved had significantly lower levels of systemic 11β-HSD1 activity at presentation when compared with patients whose synovitis persisted. This observation appears contrary to that predicted on the basis of previous work examining 11β-HSD1 activity in patients with established rheumatic diseases. In contrast to the previous results, these data raise the possibility that a high total body 11β-HSD1 activity during early arthritis may reduce the probability of disease resolution. Overall, it is still unclear whether local metabolism of endogenous GCs through the 11β-HSD system is beneficial or detrimental during synovial inflammation, and therefore further clarification is required recognising that the effects of endogenous GCs may be different at different stages of disease.

[发布机构] University:University of Birmingham;Department:School of Immunity and Infection

[关键词] R Medicine;RC Internal medicine