Inter-Alpha-Inhibitor Proteins Are Endogenous Furin Inhibitors and Provide Protection against Experimental Anthrax Intoxication

Inter-alpha-inhibitor protein (I[alpha]Ip) functions as an endogenous serine protease inhibitor in human plasma, and I[alpha]Ip levels diminish rapidly during acute inflammatory states. One potential target for I[alpha]Ip is furin, a cell-associated serine endopeptidase essential for the activation of protective antigen and the formation of anthrax lethal toxin (LT). I[alpha]Ip blocks furin activity in vitro and provides significant protection against cytotoxicity for murine peritoneal macrophages exposed to up to 500 ng/ml LT. A monoclonal antibody (MAb), 69.31, that specifically blocks the enzymatic activity of I[alpha]Ip eliminates its protective effect against LT-induced cytotoxicity. I[alpha]Ip (30 mg/kg of body weight) administered to BALB/c mice 1 hour prior to an intravenous LT challenge resulted in 71% survival after 7 days compared with no survivors among the control animals (P < 0.001). We conclude that human I[alpha]Ip may be an effective preventative or therapeutic agent against anthrax intoxication.