TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 298 LP - 305 DO - 10.1124/jpet.102.041988 VL - 305 IS - 1 AU - Mehtap Yuksel AU - Kenji Okajima AU - Mitsuhiro Uchiba AU - Hiroaki Okabe Y1 - 2003/04/01 UR - http://jpet.aspetjournals.org/content/305/1/298.abstract N2 - 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-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 the present 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 inhibitory κBα. 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-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 and those in patients with sepsis. The American Society for Pharmacology and Experimental Therapeutics ER -