title: Aceclofenac increases the synthesis of interleukin 1 receptor antagonist and decreases the production of nitric oxide in human articular chondrocytes.
abstract: OBJECTIVE
  Interleukin 1 receptor antagonist (IL-1Ra) may play an important role in cartilage degradation by inhibiting IL-1 activity and therefore blocking IL-1 stimulation of prostaglandin E2 (PGE2) synthesis. Nitric oxide (NO) formation is increased during inflammation. High concentrations of NO exert negative effects on chondrocyte functions. We investigated the possible effects of 3 different nonsteroidal antiinflammatory drugs (NSAID; aceclofenac, piroxicam, aspirin) on IL-1Ra and NO production in human articular chondrocytes.
  
  
  METHODS
  Normal and osteoarthritic (OA) cartilage samples were obtained from autopsy and prosthetic joint surgery, respectively. Chondrocytes were isolated and stimulated with 4 different stimuli: IL-1, tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), and insulin-like growth factor (IGF). The 3 NSAID were added simultaneously to each different concentration of stimulus. IL-1Ra was measured in supernatant by ELISA; nitrites were quantified by the Griess reaction; PGE2 level was measured by enzyme immunoassay.
  
  
  RESULTS
  OA samples spontaneously produced higher levels of IL-1Ra than normal samples (130+/-2.3 vs 30+/-3.1 pg/mI). IL-1, TNF-alpha, and LPS produced dose dependent increases in synthesis of IL-1Ra. In their presence, IL-1Ra was detected in supernatant at 48 h, but its highest level was measured at 144 h. The most potent stimulus was IL-1, followed by TNF-alpha. Fetal bovine serum and IGF in turn did not modify the basal levels of IL-1Ra. In contrast to piroxicam and aspirin, aceclofenac 10 microg/ml and TNF-alpha 10 ng/ml increased almost 46 times the basal amount of IL-1Ra produced by OA chondrocytes. Additionally, aceclofenac and aspirin inhibited NO synthesis. Finally, the 3 NSAID reduced the levels of PGE2 detected after stimulation with IL-1.
  
  
  CONCLUSIONS
  Proinflammatory stimuli induce IL-IRa synthesis in human articular chondrocytes. Aceclofenac may modulate PGE2 production by increasing IL-IRa production and decreasing NO synthesis. Some NSAID exert diverse prostaglandin independent effects.
authors.affiliation: Laboratorio de Investigación, Servicio de Reumatología, Hospital Juan Canalejo, A Coruña, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Maneiro
authors.forename: M J
authors.initials: MJ
authors.lastname: López-Armada
authors.forename: J L
authors.initials: JL
authors.lastname: Fernández-Sueiro
authors.forename: B
authors.initials: B
authors.lastname: Lema
authors.forename: F
authors.initials: F
authors.lastname: Galdo
authors.forename: F J
authors.initials: FJ
authors.lastname: Blanco
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides / Q000494:pharmacology; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis*; D020370:Osteoarthritis, Knee / Q000378:metabolism / Q000473:pathology; D010894:Piroxicam / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017077:Culture Media, Conditioned; D004338:Drug Combinations; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D010894:Piroxicam; D004008:Diclofenac; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D015232:Dinoprostone; D001241:Aspirin; C056498:aceclofenac