Vol. 305, Issue 1, 298-305, April 2003

Gabexate Mesilate, a Synthetic Protease Inhibitor, Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor- Production by Inhibiting Activation of Both Nuclear Factor-B and Activator Protein-1 in Human Monocytes

Mehtap Yuksel , Kenji Okajima, Mitsuhiro Uchiba and Hiroaki Okabe

Departments of Laboratory Medicine (M.Y., K.O., M.U., H.O.) and Biochemistry (M.Y.), Kumamoto University School of Medicine, Kumamoto, Japan

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