IFN-gamma 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)-alpha and to that of TNF-alpha to trigger lethal shock. Here we investigated the mechanisms underlying the P. acnes-induced sensitization to LPS and TNF-alpha and the development of individual symptoms after subsequent challenge with LPS or TNF-alpha. 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-alpha challenge. Propionibacterium acnes treatment reportedly induces both T(h)1 and T(h)17 cell development. Propionibacterium acnes-primed Il12p40(-/-) and Ifngamma(-/-) mice, while not Il17A(-/-) mice, evaded all these symptoms/signs upon LPS or TNF-alpha challenge, indicating essential requirement of IL-12-IFN-gamma axis for the sensitization to LPS and TNF-alpha. Furthermore, IFN-gamma blockade just before LPS challenge could prevent P. acnes-primed WT mice from endotoxin shock syndrome. These results demonstrated requirement of IFN-gamma to the development of endotoxin shock and suggested it as a potent therapeutic target for the treatment of septic shock.

• Authors: Kosuke Kawa, Hiroko Tsutsui, Ryosuke Uchiyama, Junko Kato, Kiyoshi Matsui, Yoichiro Iwakura, Takayuki Matsumoto, Kenji Nakanishi
• Journal: International immunology (Int Immunol) Vol. 22 Issue 3 Pg. 157-66 (Mar 2010) ISSN: 1460-2377 [Electronic] England
• PMID: 20130231 (Publication Type: Journal Article)

Chemical References

• Adjuvants, Immunologic
• Cytokines
• Inflammation Mediators
• Lipopolysaccharides
• Tumor Necrosis Factor-alpha
• Interleukin-12
• Interferon-gamma

Topics

• Adjuvants, Immunologic (pharmacology)
• Animals
• Cytokines (biosynthesis, immunology)
• Gram-Positive Bacterial Infections (immunology)
• Inflammation Mediators (immunology)
• Interferon-gamma (immunology)
• Interleukin-12 (immunology)
• Lipopolysaccharides (immunology, pharmacology)
• Lymphocyte Activation
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Propionibacterium acnes (immunology)
• Shock, Septic (immunology)
• Syndrome
• Th1 Cells (immunology)
• Tumor Necrosis Factor-alpha (immunology, pharmacology)