title: Evidence that TNF-β (lymphotoxin α) can activate the inflammatory environment in human chondrocytes.
abstract: BACKGROUND
  Inflammatory cytokines play a key role in the pathogenesis of joint diseases such as rheumatoid arthritis (RA). Current therapies target mainly tumor necrosis factor α (TNF-α) as this has proven benefits. However, a large number of patients do not respond to or become resistant to anti-TNF-α therapy. While the role of TNF-α in RA is quite evident, the role of TNF-β, also called lymphotoxin-α (LT-α), is unclear. In this study we investigated whether TNF-β and its receptor play a role in chondrocytes in the inflammatory environment.
  
  
  METHODS
  An in vitro model of primary human chondrocytes was used to study TNF-β-mediated inflammatory signaling.
  
  
  RESULTS
  Cytokine-induced inflammation enhances TNF-β and TNF-β-receptor expression in primary human chondrocytes accompanied by the up-regulation of inflammatory (cyclooxygenase-2), matrix degrading(matrix metalloproteinase-9 and -13) and apoptotic (p53, cleaved caspase-3) signaling pathways, all known to be regulated by NF-κB. In contrast, anti-TNF-β, similar to the natural NF-κB inhibitor (curcumin, diferuloylmethane) or the knockdown of NF-κB by using antisense oligonucleotides (ASO), suppressed IL-1β-induced NF-κB activation and its translocation to the nucleus, and abolished the pro-inflammatory and apoptotic effects of IL-1β. This highlights,at least in part, the crucial role of NF-κB in TNF-β-induced-inflammation in cartilage, similar to that expected for TNF-α. Finally, the adhesiveness between TNF-β-expressing T-lymphocytes and the responding chondrocytes was significantly enhanced through a TNF-β-induced inflammatory microenvironment.
  
  
  CONCLUSIONS
  These results suggest for the first time that TNF-β is involved in microenvironment inflammation in chondrocytes during RA parallel to TNF-α, resulting in the up-regulation of NF-κB signaling and activation of pro-inflammatory activity.
authors.forename: Constanze
authors.initials: C
authors.lastname: Buhrmann
authors.forename: Parviz
authors.initials: P
authors.lastname: Shayan
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000276:immunology; D019902:Chondrocytes / Q000276:immunology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000276:immunology* / Q000378:metabolism; D016253:Microscopy, Immunoelectron; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection
chemical_list: D053583:Interleukin-1beta; D008233:Lymphotoxin-alpha; D016328:NF-kappa B