Tumor necrosis factor inhibition modulates thrombospondin-1 expression in human inflammatory joint disease through altered NR4A2 activity.

Abstract

We examined thrombospondin-1 (THBS1, alias TSP-1) expression in human synovial tissue (ST) during the resolution phase of chronic inflammation and elucidated its transcriptional regulation by the orphan receptor 4A2 (NR4A2). In vivo, rheumatoid arthritis (RA) serum and ST revealed altered expression levels and tissue distribution of TSP-1. After anti-tumor necrosis factor therapy, a reciprocal relationship between TSP-1 and NR4A2 expression levels was measured in patients with clinical and ST responses to biological treatment. In vitro, primary RA fibroblast-like synoviocytes (FLSs) expressed minimal TSP-1 mRNA levels with high transcript levels of NR4A2, vascular endothelial growth factor (VEGF), and IL-8 measured. Hypoxic modulation of RA FLSs resulted in inverse expression levels of TSP-1 compared with NR4A2, IL-8, and VEGF. Ectopic NR4A2 expression led to reduced TSP-1 mRNA and protein levels with concomitant increases in proangiogenic mediators. NR4A2 transcriptional activity, independent of DNA binding, repressed the hTSP-1 promoter leading to reduced mRNA and protein release in immortalized K4IM FLSs. Bioinformatic and deletion studies identified a 5' region of the TSP-1 promoter repressed by NR4A2 and proangiogenic transcription factors, including NF-κB and Ets1/2. Stable depletion of NR4A2 levels resulted in a shift in the TSP-1/VEGF expression ratio. Thus, modulation of TSP-1 expression is achieved through anti-tumor necrosis factor therapy effects on specific transcriptional networks, suggesting that enhanced TSP-1 expression may help restore tissue homeostasis during resolution of inflammation.

• Authors: Jason P McMorrow, Daniel Crean, Martina Gogarty, Aisling Smyth, Mary Connolly, Eoin Cummins, Douglas Veale, Ursula Fearon, Paul P Tak, Oliver Fitzgerald, Evelyn P Murphy
• Journal: The American journal of pathology (Am J Pathol) Vol. 183 Issue 4 Pg. 1243-1257 (Oct 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23933487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Angiogenesis Inducing Agents
• NR4A2 protein, human
• Nuclear Receptor Subfamily 4, Group A, Member 2
• Thrombospondin 1
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor A
• DNA

Topics

• Adult
• Aged
• Aged, 80 and over
• Angiogenesis Inducing Agents (metabolism)
• Arthritis, Rheumatoid (genetics, pathology)
• Cells, Cultured
• DNA (metabolism)
• Fibroblasts (metabolism, pathology)
• Gene Expression Regulation
• Humans
• Inflammation (pathology)
• Joints (pathology)
• Middle Aged
• Nuclear Receptor Subfamily 4, Group A, Member 2 (blood, genetics, metabolism)
• Promoter Regions, Genetic (genetics)
• Protein Binding (genetics)
• Synovial Membrane (metabolism, pathology)
• Thrombospondin 1 (blood, genetics)
• Transcription, Genetic
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)
• Vascular Endothelial Growth Factor A (metabolism)