title: Preferential induction of prodestructive matrix metalloproteinase-1 and proinflammatory interleukin 6 and prostaglandin E2 in rheumatoid arthritis synovial fibroblasts via tumor necrosis factor receptor-55.
abstract: OBJECTIVE
  To assess expression and individual functional relevance of tumor necrosis factor receptor 55 (TNF-R55) and TNF-R75 in rheumatoid arthritis (RA) and osteoarthritis (OA) synovial fibroblasts (SFB).
  
  
  METHODS
  Seventh to 9th passage RA SFB and OA SFB were analyzed for TNF-R expression by FACS. The SFB were then stimulated with TNF-a (1-10 ng/ml) or agonistic anti-TNF-R55 (HTR-9) and anti-TNF-R75 (UTR-1) monoclonal antibodies (1-25 micro g/ml each). Matrix metalloproteinase-1 (MMP-1), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), interleukin 6 (IL-6), and prostaglandin E(2) (PGE(2)) in culture supernatants were quantified by ELISA, and DNA fragmentation by TUNEL assay.
  
  
  RESULTS
  RA SFB variably expressed TNF-R55 (7.2 +/- 2.2% positive cells, mean +/- SEM) and TNF-R75 (0.6 +/- 0.3%), similarly to OA SFB (6.8 +/- 2.1% and 1.6 +/- 0.8%, respectively). RA SFB constitutively secreted large amounts of TIMP-1 (1700 ng/ml), but only small amounts of MMP-1 (23.7 ng/ml), IL-6 (4.4 ng/ml), and PGE(2) (0.34 ng/ml). OA SFB secreted comparable amounts of TIMP-1 (2470 ng/ml), MMP-1 (37 ng/ml), and IL-6 (5.0 ng/ml), but significantly higher amounts of PGE(2) (0.58 ng/ml; p </= 0.05). TNF-a stimulation induced IL-6 secretion by RA SFB (3-fold) and OA SFB (4-fold), as well as MMP-1 secretion (RA, 85-fold; OA, 29-fold), with significant differences between RA and OA. This was exclusively mediated by separate stimulation with agonistic anti-TNF-R55 Mab. Strikingly, RA SFB were completely unresponsive to TIMP-1 mRNA and protein induction by TNF-a, whereas TIMP-1 mRNA and/or protein in OA SFB was significantly upregulated by TNF-a (2-fold; p </= 0.05, OA > RA) and by separate stimulation of both TNF receptors. TNF-a-induced PGE(2) release by RA SFB (92-fold) and OA SFB (56-fold) was mediated by both TNF receptors; however, predominantly by TNF-R55. DNA fragmentation was induced exclusively by high concentrations of anti-TNF-R55 Mab and only in RA SFB.
  
  
  CONCLUSIONS
  These results indicate preferential induction of prodestructive and proinflammatory mediators in RA SFB by the TNF-R55, with potential implications for understanding the pathogenesis of RA and the development of more specific therapeutic strategies.
authors.affiliation: Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Saifeddin
authors.initials: S
authors.lastname: Alsalameh
authors.forename: Rayya J
authors.initials: RJ
authors.lastname: Amin
authors.forename: Elke
authors.initials: E
authors.lastname: Kunisch
authors.forename: Hugo E
authors.initials: HE
authors.lastname: Jasin
authors.forename: Raimund W
authors.initials: RW
authors.lastname: Kinne
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D008875:Middle Aged; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013583:Synovial Membrane / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D019715:Tissue Inhibitor of Metalloproteinase-1; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone