RT Journal Article SR Electronic 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 FD American Society for Pharmacology and Experimental Therapeutics SP 298 OP 305 DO 10.1124/jpet.102.041988 VO 305 IS 1 A1 Mehtap Yuksel A1 Kenji Okajima A1 Mitsuhiro Uchiba A1 Hiroaki Okabe YR 2003 UL http://jpet.aspetjournals.org/content/305/1/298.abstract AB 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