UvA-DARE ( Digital Academic Repository ) Prostaglandin E-2 Synthesizing Enzymes in Rheumatoid Arthritis B Cells and the Effects of B Cell Depleting Therapy on Enzyme Expression

Introduction: B cells may play an important role in promoting immune activation in the rheumatoid synovium and can produce prostaglandin E2 (PGE2) when activated. In its turn, PGE2 formed by cyclooxygenase (COX) and microsomal prostaglandin E2 synthase 1 (MPGES1) contributes to the rheumatoid arthritis (RA) pathological process. Therapeutic depletion of B cells results in important improvement in controlling disease activity in rheumatoid patients. Therefore we investigated the expression of PGE2 pathway enzymes in RA B cells and evaluated the effects of B cell depleting therapy on their expression in RA tissue. Methods: B cells expressing MPGES1 and COX-2 were identified by flow cytometry in in vitro stimulated and control mononuclear cells isolated from synovial fluid and peripheral blood of RA patients. Synovial biopsies were obtained from 24 RA patients before and at two consecutive time points after rituximab therapy. Expression of MPGES1, COX-1 and COX-2, as well as interleukin (IL)-1b and IL-6, known inducers of MPGES1, was quantified in immunostained biopsy sections using computerized image analysis. Results: Expression of MPGES1 or COX-2 was significantly upregulated upon stimulation of B cells from blood and synovial fluid while control cells displayed no detectable enzymes. In synovial biopsy sections, the expression of MPGES1, COX-1 or COX-2 was resistant to rituximab therapy at 8 or 16 weeks after start of treatment. Furthermore expression of IL-1b in the synovial tissue remained unchanged, while IL-6 tended to decrease after therapy. Conclusions: Therapy with B cell depleting agents, although efficient in achieving good clinical and radiographic response in RA patients, leaves important inflammatory pathways in the rheumatoid synovium essentially unaffected. Citation: Gheorghe KR, Thurlings RM, Westman M, Boumans MJ, Malmström V, et al. (2011) Prostaglandin E2 Synthesizing Enzymes in Rheumatoid Arthritis B Cells and the Effects of B Cell Depleting Therapy on Enzyme Expression. PLoS ONE 6(1): e16378. doi:10.1371/journal.pone. 0016378 Editor: Mehrdad Matloubian, University of California San Francisco, United States of America Received October 6, 2010; Accepted December 13, 2010; Published January 27, 2011 Copyright: 2011 Gheorghe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by The Swedish Research Council, The Swedish Rheumatism Association, King Gustaf V 80 years Foundation, The Swedish Society of Medicine, Marianne and Marcus Wallenberg foundation, Karolinska Institutet Foundation and European Commission Sixth Framework Program Autocure, the Center for Translational Molecular Medicine (TRACER), and the Dutch Arthritis Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have read the journal’s policy and have the following conflicts: Profesor Tak has served as a consultant for Roche. Associate Professor Per-Johan Jakobsson is a member of the board of directors of NovaSAID. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: per-johan.jakobsson@ki.se