Extracellular Human Thioredoxin-1 Inhibits Lipopolysaccharide-induced Interleukin-1β Expression in Human Monocyte-derived Macrophages

• Published in: The Journal of biological chemistry Vol. 280; no. 48; pp. 40310 - 40318
• Main Authors: Billiet, Ludivine, Furman, Christophe, Larigauderie, Guilhem, Copin, Corinne, Brand, Korbinian, Fruchart, Jean-Charles, Rouis, Mustapha
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 02-12-2005
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M503644200

Oxidative stress plays an important role in atherosclerotic vascular disease, and several recent studies were focused on thioredoxin-1 (Trx-1) and its potential protective role against oxidative stress. Since human monocyte-derived macrophages (HMDM) are important cells in several inflammatory diseases including atherosclerosis, we conducted this study to evaluate the impact of extracellular recombinant human Trx-1 (rhTrx-1) on gene expression in lipopolysaccharide-activated HMDM. Our results showed that rhTrx-1 was capable of reducing interleukin (IL)-1β mRNA and protein synthesis in a dose-dependent manner. This effect was partly mediated through a reduction of NF-κB activation as analyzed by transient transfection and gel shift assays. In addition, we showed that the attenuation of NF-κB activity was the result of the reduction of both p50 and p65 subunit mRNA and protein synthesis on one hand and of the induction of I-κBα mRNA and protein expression on the other hand. Moreover, inhibition of endogenous Trx-1 mRNA was also observed, suggesting a contribution to the diminution of NF-κB activity since endogenous Trx-1, in contrast to the exogenous Trx-1, activates the NF-κB system. Finally, H2O2-oxidized rhTrx-1 reduced IL-1β mRNA synthesis in lipopolysaccharide-activated HMDM. This result highly suggested that the rhTrx-1 used in this study could be oxidized in the culture medium and, in turn, reduced IL-1β mRNA and protein synthesis. Taken together, these data indicated a potential new mechanism through which extracellular rhTrx-1 exerts an anti-inflammatory function in HMDM.