IFN-gamma is a master regulator of endotoxin shock syndrome in mice primed with heat-killed Propionibacterium acnes.
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.
Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Kosuke
K
Kawa
Hiroko
H
Tsutsui
Ryosuke
R
Uchiyama
Junko
J
Kato
Kiyoshi
K
Matsui
Yoichiro
Y
Iwakura
Takayuki
T
Matsumoto
Kenji
K
Nakanishi
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D016908:Gram-Positive Bacterial Infections / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011425:Propionibacterium acnes / Q000276:immunology*; D012772:Shock, Septic / Q000276:immunology*; D013577:Syndrome; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma