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

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-alpha (TNF-alpha) plays a critical role. We demonstrated that gabexate mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-alpha production in rats. In this study, we analyzed the mechanism(s) by which gabexate mesilate inhibits LPS-induced TNF-alpha production in human monocytes in vitro. Gabexate mesilate inhibited the production of TNF-a in monocytes stimulated with LPS. Gabexate mesilate inhibited both the binding of nuclear factor-kappaB (NF-kappaB) to target sites and the degradation of IkappaBalpha. Gabexate mesilate also inhibited both the binding of activator protein-1 (A-P-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-a production in human monocytes by inhibiting activation of both NF-kappaB and AP-1. Inhibition of TNF-alpha production by gabexate mesilate might explain, at least partly, its therapeutic effects in animals given LPS in patients with sepsis. (C) 2003 Elsevier B.V. All rights reserved.