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Open Access Research article

Evidence that TNF-β (lymphotoxin α) can activate the inflammatory environment in human chondrocytes

Constanze Buhrmann1, Parviz Shayan2, Bharat B Aggarwal3 and Mehdi Shakibaei1*

Author Affiliations

1 Musculoskeletal Research Group, Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336, Munich, Germany

2 Investigating Institute of Molecular Biological System Transfer, Tehran 1417863171, Iran

3 Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Unit 143, 1515 Holcombe Boulevard, Houston, TX 77030, USA

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Arthritis Research & Therapy 2013, 15:R202  doi:10.1186/ar4393

Published: 28 November 2013

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 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.