Protection from septic shock by neutralization of macrophage migration inhibitory factor

Identification of new therapeutic targets for the management of septic shoc k remains imperative as all investigational therapies, including anti-tumor necrosis factor (TNF) and anti-interleukin (IL)-1 agents, have uniformly f ailed to lower the mortality of critically ill patients with severe sepsis. We report here that macrophage migration inhibitory factor (MIF) is a crit ical mediator of septic shock. High concentrations of MIF were detected in the peritoneal exudate fluid and in the systemic circulation of mice with b acterial peritonitis. Experiments performed in TNF alpha knockout mice allo wed a direct evaluation of the part played by MIF in sepsis in the absence of this pivotal cytokine of inflammation. Anti-MIF antibody protected TNF a lpha knockout from lethal peritonitis induced by cecal ligation and punctur e (CLP), providing evidence of an intrinsic contribution of MIF to the path ogenesis of sepsis. Anti-MIF antibody also protected normal mice from letha l peritonitis induced by both CLP and Escherichia coli, even when treatment was started up to 8 hours after CLP. Conversely co-injection of recombinan t MIF and E. coli markedly increased the lethality of peritonitis. Finally, high concentrations of MIF were detected in the plasma of patients with se vere sepsis or septic shock. These studies define a critical part for MIF i n the pathogenesis of septic shock and identify a new target for therapeuti c intervention.