Effects of anti-rheumatic treatments on the prostaglandin E₂ biosynthetic pathway in synovial tissue and synovial fluid cells from patients with rheumatoid arthritis

Microsomal prostaglandin E synthase (mPGES)-1 is upregulated in experimental arthritis and is markedly expressed in synovial tissue from patients with rheumatoid arthritis (RA), suggesting its important role of in the pathogenesis of inflammatory arthritis. However, the effects of current anti-rheumatic therapies on mPGES-1 expression have not been examined.

To study the effects of anti-tumour necrosis factor (TNF) alpha blockers and glucocorticoids on prostaglandin (PG) E₂ biosynthesis and mPGES-1 expression in synovial fluid mononuclear cells (SFMC) and synovial tissue from RA patients.

Synovial tissues were obtained from 18 RA patients before and after treatment with TNF-blockers (infliximab and etanercept) and from 16 patients before and after intra-articular injection of steroids. SFMC were obtained from eight RA patients. In vitro effects of TNF-blockers and dexamethasone (Dex) on mPGES-1 expression in SFMC were examined by flow cytometry. PGE₂ levels in culture supernatants were analyzed by enzyme immunoassay. Immunohistological analysis and double immunofluorescence were performed using antibody against mPGES-1, cyclooxygenase (COX) and CD163.

Treatment of SFMC with TNF-blockers or Dex decreased lipopolysaccharide-induced mPGES-1 and COX-2 expression in CD14⁺ monocytes and PGE₂ synthesis in culture supernatants. Double immunofluorescence revealed that mPGES-1 and COX-2 were co-localized in SFMC and in synovial tissue cells. Local treatment with steroids significantly reduced the mPGES-1, COX-2 and COX-1 expression in synovial tissue. However, neither mPGES-1 nor COX-2 expression in RA synovial tissues were significantly affected by anti-TNF therapy.

In vitro, both TNF-blockers and Dex suppressed mPGES-1 in SFMC. In RA synovial tissue, local steroids but not TNF-blockade downregulate mPGES-1. These data provide support to the use of combination of TNF-blockade and inhibitors of PGE₂ production for optimal anti-inflammatory achievement.

Affiliations

1. Department of Medicine, Rheumatology Unit, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden

   • M Korotkova
   • , M Westman
   • , KR Gheorghe
   • , E af Klint
   • , C Trollmo
   • , A-K Ulfgren
   • , L Klareskog
   •  & P-J Jakobsson

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