Evidence that TNF-beta ( lymphotoxin alpha) can activate the inflammatory environment in human chondrocytes

Buhrmann, Constanze; Shayan, Parviz; Aggarwal, Bharat B. und Shakibaei, Mehdi (2013): Evidence that TNF-beta ( lymphotoxin alpha) can activate the inflammatory environment in human chondrocytes. In: Arthritis Research & Therapy 15:R202

Abstract

Introduction: Inflammatory cytokines play a key role in the pathogenesis of joint diseases such as rheumatoid arthritis (RA). Current therapies target mainly tumor necrosis factor alpha (TNF-alpha) as this has proven benefits. However, a large number of patients do not respond to or become resistant to anti-TNF-alpha therapy. While the role of TNF-alpha in RA is quite evident, the role of TNF-alpha, also called lymphotoxin-alpha (LT-alpha), is unclear. In this study we investigated whether TNF-beta 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-beta-mediated inflammatory signaling. Results: Cytokine-induced inflammation enhances TNF-beta and TNF-beta-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-kappa B. In contrast, anti-TNF-beta, similar to the natural NF-kappa B inhibitor (curcumin, diferuloylmethane) or the knockdown of NF-kappa B by using antisense oligonucleotides (ASO), suppressed IL-1 beta-induced NF-kappa B activation and its translocation to the nucleus, and abolished the pro-inflammatory and apoptotic effects of IL-1 beta. This highlights, at least in part, the crucial role of NF-kappa B in TNF-beta-induced-inflammation in cartilage, similar to that expected for TNF-alpha. Finally, the adhesiveness between TNF-beta-expressing T-lymphocytes and the responding chondrocytes was significantly enhanced through a TNF-beta-induced inflammatory microenvironment. Conclusions: These results suggest for the first time that TNF-beta is involved in microenvironment inflammation in chondrocytes during RA parallel to TNF-alpha, resulting in the up-regulation of NF-kappa B signaling and activation of pro-inflammatory activity.

• Dokumententyp: Zeitschriftenartikel
• Publikationsform: Publisher's Version
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1478-6354
• Sprache: Englisch