Effects of Antithrombin III on Tumor Necrosis Factor- α and Interleukin-1 β Synthesis in Vascular Smooth Muscle Cells

Abstract

In the course of sepsis, severe coagulopathy and disseminated intravascular coagulation (DIC) are common events. Therefore, substances known to interfere with the coagulation cascade have been studied in animal models of sepsis. Among them, antithrombin III (AT III) was reported to be a promising therapeutic tool because it exhibited anti-inflammatory properties in addition to its anticoagulative effects. In our studies using vascular smooth muscle cells (VSMC) as a monoculture model, contradictory effects of AT III on the release of the proinflammatory agonists tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were found. Whereas AT III inhibited the lipopolysaccharide (LPS)-induced production of these cytokines on both the transcriptional and the translational levels when given at higher concentrations (5 or 10 U/ml), lower amounts of AT III did not show this suppressive effect. In contrast, 0.5, 1, and 5 U/ml AT III led to an enhancement of TNF-α synthesis when combined with LPS. To date, we cannot provide a mechanism to explain the AT III-promoted modulation of TNF-α and IL-1β generation in VSMC. However, with respect to its potential therapeutic benefit in systemic inflammatory conditions, AT III should not be regarded strictly as an anti-inflammatory modulator.