Abstract
IntroductionRheumatoid arthritis (RA) is a chronic inflammatory disease in which prostaglandin E2 (PGE2) displays an important pathogenic role. The enzymes involved in its synthesis are highly expressed in the inflamed synovium, while little is known about 15- prostaglandin dehydrogenase (15-PGDH) that metabolizes PGE2. Here we aimed to evaluate the localization of 15-PGDH in the synovial tissue of healthy individuals or patients with inflammatory arthritis and determine the influence of common RA therapy on its expression.MethodsSynovial tissue specimens from healthy individuals, psoriatic arthritis, ostheoarthritis and RA patients were immunohistochemically stained to describe the expression pattern of 15-PGDH. In addition, the degree of enzyme staining was evaluated by computer analysis on stained synovial biopsies from two groups of RA patients, before and after RA specific treatment with either intra-articular glucocorticoids or oral methotrexate therapy. Prostaglandins derived from the cyclooxygenase (COX) pathway were determined by liquid-chromatography mass spectrometry in supernatants from interleukin (IL) 1β-activated fibroblast-like synoviocytes (FLS) treated with methotrexate.Results15-PGDH was present in healthy and inflamed synovial tissue, mainly in lining macrophages, fibroblasts and vessels. Intra-articular glucocorticoids showed a trend towards reduced 15-PGDH expression in RA synovium (p = 0.08) while methotrexate treatment left the PGE2 pathway unaltered both in biopsies ex vivo and in cultured FLS.ConclusionsEarly methotrexate therapy has little influence on the expression of 15-PGDH and on any of the PGE2 synthesizing enzymes or COX-derived metabolites. Thus therapeutic strategies involving blocking induced PGE2 synthesis may find a rationale in additionally reducing local inflammatory mediators.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disease in which prostaglandin E2 (PGE2) displays an important pathogenic role
Most of the prostaglandin inactivation occurs through the action of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which converts PGE2 to a metabolite with greatly reduced biological activity [6] and is the main mechanism for PGE2 clearance. 15- prostaglandin dehydrogenase (15-PGDH) is ubiquitously expressed in most mammalian tissues [6]
Its presence in RA synovial tissue was prominent in the synovial lining and in scattered sublining macrophages and inflammatory infiltrates as well as vessels
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease in which prostaglandin E2 (PGE2) displays an important pathogenic role. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and extensive proliferation within the joint synovial tissue and by recruitment and activation of immune cells and subsequent cartilage and bone destruction. Rheumatoid joint displays an activated prostaglandin E2 (PGE2) pathway, and there are high levels of this mediator in the synovial fluid and strong expression in the synovium of its synthesizing tumor necrosis factor (TNF) and interleukin-1-beta (IL1b), that orchestrate the pathological events in this disease are known inducers of mPGES-1 and COX-2 expression [5]. Reduced expression of 15-PGDH contributes to the elevated PGE2 levels observed in the systemic inflammatory response [13] or in the inflamed mucosa of patients with inflammatory bowel disease [8]
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