GTC Biotherapeutics (fka GTCB)

[DewDiligence]

Antithrombin Inhibits Lipopolysaccharide-Induced TNF-Alpha Production by Monocytes In Vitro Through Inhibition of Egr-1 Expression

[This paper addresses the mechanism of the anti-inflammatory property of antithrombin, which may play an important role in DIC.]

http://tinyurl.com/yrskhx

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J Thromb Haemost. 2007 Dec 11.

Komura H, Uchiba M, Mizuochi Y, Arai M, Harada N, Katsuya H, Okajima K.

Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Background: Antithrombin (AT) improves the outcome of septic patients with intravascular coagulation. However, the mechanisms underlying the therapeutic benefits of AT are not fully understood. Tumour necrosis factor-alpha (TNF-alpha) plays a critical role in the development of organ failure and intravascular coagulation in sepsis. This study aimed to elucidate a molecular mechanism by which AT inhibits TNF-alpha production.

Results: AT (3 U/ml) inhibited TNF-alpha production by monocytes stimulated with lipopolysaccharide (LPS). Conversely, chemically modified AT that lacks affinity for heparin did not. AT inhibited the phosphorylation of extracellular signal-regulated protein kinases (ERK) 1/2 and decreased the expression of early growth response factor-1 (Egr-1) in LPS-stimulated monocytes. However, it did not affect the activation of either nuclear factor-kappaB or activator protein-1. Pre-treatment with KT5720, a protein kinase A inhibitor, reversed the inhibitory effect of AT on the LPS-induced phosphorylation of ERK1/2. Although 2 U/ml AT slightly inhibited TNF-alpha production by LPS-stimulated monocytes, it significantly inhibited TNF-alpha production in the presence of a low concentration of beraprost, a stable derivative of prostacyclin.

Conclusions: These observations suggest that AT might inhibit LPS-induced production of TNF-alpha by inhibiting the increase in Egr-1 expression in monocytes via interaction with heparin-like substances expressed on the cell surface.
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