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

Abstract

Inter-alpha-inhibitor protein (IalphaIp) functions as an endogenous serine protease inhibitor in human plasma, and IalphaIp levels diminish rapidly during acute inflammatory states. One potential target for IalphaIp is furin, a cell-associated serine endopeptidase essential for the activation of protective antigen and the formation of anthrax lethal toxin (LT). IalphaIp 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 IalphaIp eliminates its protective effect against LT-induced cytotoxicity. IalphaIp (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 IalphaIp may be an effective preventative or therapeutic agent against anthrax intoxication.