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International Immunology

Year: 2010  |  Volume: 22  |  Issue: 3  |  Page No.: 157 - 166

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

K Kawa, H Tsutsui, R Uchiyama, J Kato, K Matsui, Y Iwakura, T Matsumoto and K. Nakanishi

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)- and to that of TNF- to trigger lethal shock. Here we investigated the mechanisms underlying the P. acnes-induced sensitization to LPS and TNF- and the development of individual symptoms after subsequent challenge with LPS or TNF-. 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- challenge. Propionibacterium acnes treatment reportedly induces both Th1 and Th17 cell development. Propionibacterium acnes-primed Il12p40–/– and Ifn–/– mice, while not Il17A–/– mice, evaded all these symptoms/signs upon LPS or TNF- challenge, indicating essential requirement of IL-12–IFN- axis for the sensitization to LPS and TNF-. Furthermore, IFN- blockade just before LPS challenge could prevent P. acnes-primed WT mice from endotoxin shock syndrome. These results demonstrated requirement of IFN- to the development of endotoxin shock and suggested it as a potent therapeutic target for the treatment of septic shock.

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