Gabexate mesilate, a synthetic protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α production by inhibiting activation of both nuclear factor-κB and activator protein-1 in human monocytes
2003
Abstract Gabexate mesilate, a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation (DIC) in which tumor necrosis factor-α (TNF-α) plays a critical role. We demonstrated that gabexate mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-α production in rats. In this study, we analyzed the mechanism(s) by which gabexate mesilate inhibits LPS-induced TNF-α production in human monocytes in vitro. Gabexate mesilate inhibited the production of TNF-α in monocytes stimulated with LPS. Gabexate mesilate inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of IκBα. Gabexate mesilate also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase (MAPK) pathways. These observations strongly suggest that gabexate mesilate inhibits LPS-induced TNF-α production in human monocytes by inhibiting activation of both NF-κB and AP-1. Inhibition of TNF-α production by gabexate mesilate might explain, at least partly, its therapeutic effects in animals given LPS in patients with sepsis.
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