title: Effects of antirheumatic treatments on the prostaglandin E2 biosynthetic pathway.
abstract: OBJECTIVE
  Microsomal prostaglandin E synthase 1 (mPGES-1) is up-regulated in experimental arthritis and markedly expressed in synovial tissue biopsy samples from patients with rheumatoid arthritis (RA). This study was carried out to determine the effects of tumor necrosis factor (TNF) blockers and glucocorticoids on mPGES-1 and cyclooxygenase (COX) expression, as well as biosynthesis of PGE(2) in rheumatoid joints.
  
  
  METHODS
  In vitro effects of TNF blockers and dexamethasone on the PGE(2) biosynthetic pathway were examined in RA synovial fluid mononuclear cells (SFMCs) by flow cytometry. PGE(2) levels in culture supernatants were measured by enzyme immunoassay. Expression of enzymes responsible for PGE(2) synthesis ex vivo was evaluated by immunohistochemistry in synovial biopsy samples obtained from 18 patients before and after treatment with TNF blockers and from 16 patients before and after intraarticular treatment with glucocorticoids. Double immunofluorescence was performed using antibodies against mPGES-1, COX-1, COX-2, and CD163.
  
  
  RESULTS
  Double immunofluorescence revealed that mPGES-1 and COX-2 were colocalized in SFMCs as well as in RA synovial tissue cells. The addition of either TNF blockers or dexamethasone suppressed lipopolysaccharide-induced mPGES-1 and COX-2 expression in synovial fluid monocyte/macrophages in vitro and decreased the production of PGE(2). Intraarticular treatment with glucocorticoids significantly reduced both mPGES-1 and COX-2 expression in arthritic synovial tissue ex vivo. The number of COX-1-expressing cells in synovial tissue was also significantly decreased by glucocorticoid treatment. In contrast, neither mPGES-1 nor COX-2 expression in synovial tissue was significantly suppressed by anti-TNF therapy.
  
  
  CONCLUSIONS
  These data are the first to demonstrate the effects of antirheumatic treatments on mPGES-1 expression in RA and suggest that the inhibition of PGE(2) biosynthesis, preferably by targeting mPGES-1, might complement anti-TNF treatment for optimal antiinflammatory results in RA.
authors.affiliation: Rheumatology Research Laboratory, CMM L8-04, Karolinska Institutet, Karolinska University Hospital, Stockholm S-17176, Sweden. Marina.Korotkova@cmm.ki.se
authors.forename: Marina
authors.initials: M
authors.lastname: Korotkova
authors.forename: Marie
authors.initials: M
authors.lastname: Westman
authors.forename: Karina R
authors.initials: KR
authors.lastname: Gheorghe
authors.forename: Erik
authors.initials: E
authors.lastname: af Klint
authors.forename: Christina
authors.initials: C
authors.lastname: Trollmo
authors.forename: Ann Kristin
authors.initials: AK
authors.lastname: Ulfgren
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D000069285:Infliximab; D007270:Injections, Intra-Articular; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000071876:Prostaglandin-E Synthases; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015415:Biomarkers; D004338:Drug Combinations; D005938:Glucocorticoids; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D000068800:Etanercept