mPGES-1 and the PGE2 pathway in arthritis

Abstract

Prostaglandins are a group of lipid mediators derived from essential fatty acids that act on cells in close proximity of their synthesis. Prostaglandins are produced in a cell specific manner by a variety of cells in response to physiological or pathological stimulation. Microsomal prostaglandin E synthase 1 (mPGES-1) constitutes an enzyme responsible for the inducible production of prostaglandin E2 (PGE2), a prostaglandin thought to play an important role in the pathogenesis of arthritis.

In our studies we have demonstrated a pronounced expression of mPGES-1 and cyclooxygenase1 and -2 (COX-1 and -2), the enzymes upstream of mPGES-1, in synovial tissue from patients with rheumatoid arthritis (RA). mPGES-1 was located in synovial fibroblasts and macrophages, but no expression could be detected in B- or T-lymphocytes. During recent years, RA patients have been successfully treated with therapies depleting tumor necrosis factor (TNF). Despite the ability of TNF to induce the expression of mPGES-1 we could not detect a significant decrease of mPGES- 1 expression in synovial tissue from RA patients that had received therapy with TNF blockade. Another common treatment for RA is local injection of steroids.

In synovial tissue biopsies from patients that received intraarticular steroid injection we could demonstrate a significant suppression of mpGES-1, COX-1 and COX-2 protein expression. In contrast, in vitro cultures of synovial fluid leukocytes stimulated with endotoxin, the addition of TNF blockers or steroids resulted in similar significant suppressive effects on the expression of COX-2 and mPGES-1 in monocytes. However, neither therapy with TNF blockade nor steroid treatment resulted in decreased expression of COX-1 in these cultures.

Expression of COX isoenzymes has previously been described in both B-lymphocytes and Tlymphocytes. We demonstrated expression of mPGES-1 in stimulated synovial fluid Blymphocytes and peripheral blood B-lymphocytes. In these cells the expression of COX-1 and COX-2 were also induced after in vitro stimulation. However, we could not detect a basal expression of mPGES-1 or COX isoenzymes in unstimulated B-lymphocytes. Neither could expression of mPGES-1 be detected in unstimulated or stimulated T-lymphocytes.

Several experimental models of RA exist, enabling a more controlled environment in studying the pathological mechanism underlying arthritis. Using one such model, collagen induced arthritis (CIA), we investigated the expression of mPGES-1 and the COX isoenzymes during the development of arthritis. Already at one week before onset of clinical disease we could demonstrate an increased expression of mPGES-1, this increase being sustained throughout the course of disease. Concomitantly, we could demonstrate increase of both COX-1 and COX-2 expression. All three enzymes were mainly located in fibroblast-like cells, but their expressions were also evident in macrophages and, COX-2 was also expressed in Blymphocytes.

The presence of mPGES-1 in synovial tissue during RA and the finding that this enzyme is expressed early on in the disease process of experimental arthritis suggest an important role for mPGES-1-derived PGE2 in the pathogenesis of RA.