IFN-γ is a master regulator of endotoxin shock syndrome in mice primed with heat-killed Propionibacterium acnes

Abstract

Hyper-coagulation, hypothermia, systemic inflammatory responses and shock are major clinical manifestations of endotoxin shock syndrome in human. As previously reported, mice primed with heat-killed Propionibacterium acnes are highly susceptible to the action of LPS to induce tumour necrosis factor (TNF)-α and to that of TNF-α to trigger lethal shock. Here we investigated the mechanisms underlying the P. acnes-induced sensitization to LPS and TNF-α and the development of individual symptoms after subsequent challenge with LPS or TNF-α. Propionibacterium acnes-primed wild-type (WT) mice, but not naive mice, exhibited hyper-coagulation with elevated levels of thrombin-antithrombin complexes and anti-fibrinolytic plasminogen activator inhibitor 1 in their plasma, hypothermia, systemic inflammatory responses and high mortality rate after LPS or TNF-α challenge. Propionibacterium acnes treatment reportedly induces both Th1 and Th17 cell development. Propionibacterium acnes-primed Il12p40-/- and Ifnγ-/- mice, while not Il17A-/- mice, evaded all these symptoms/signs upon LPS or TNF-a challenge, indicating essential requirement of IL-12-IFN-γ axis for the sensitization to LPS and TNF-α. Furthermore, IFN-γ blockade just before LPS challenge could prevent P. acnes-primed WT mice from endotoxin shock syndrome. These results demonstrated requirement of IFN-g to the development of endotoxin shock and suggested it as a potent therapeutic target for the treatment of septic shock. © The Japanese Society for Immunology. 2010. All rights reserved.