Extracellular human thioredoxin-1 inhibits lipopolysaccharide-induced interleukin-1β expression in human monocyte-derived macrophages

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)-1 beta mRNA and protein synthesis in a dose-dependent manner. This effect was partly mediated through a reduction of NF-kappa B activation as analyzed by transient transfection and gel shift assays. In addition, we showed that the attenuation of NF-kappa B 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-kappa Ba 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-kappa B activity since endogenous Trx-1, in contrast to the exogenous Trx-1, activates the NF-kappa B system. Finally, H2O2x-oxidized rhTrx-1 reduced IL-1 beta 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-1 beta 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.