Roles of gamma interferon and tumor necrosis factor-alpha in shiga toxin lethality.
Shiga toxins (Stxs) have been specifically implicated as a causal factor of hemolytic uremic syndrome and acute encephalopathy. The first step of Stx-induced brain damage is considered to injure endothelial cells cooperating with tumor necrosis factor-alpha (TNF-alpha). Gamma interferon (IFN-gamma) is one of the proinflammatory cytokines as well as TNF-alpha is critical in activation of endothelial cells. Therefore we focused on the possibility of IFN-gamma-mediated lethality of Stx1 or Stx2 in mice. All of mice died within 3-4 days after injection with 400 ng of Stx1 and 37.5% of mice, which had been injected with 133 ng, survived. In contrast, a lethal dose of Stx2 was 40 times lower than that of Stx1. When mice were given 400 ng of Stx1 or 10 ng of Stx2, IFN-gamma mRNA was detected in the spleens 24h after injection. Moreover, when mice were injected with 133 ng of Stx1 or 3.3 ng of Stx2, survival rates of IFN-gamma-deficient mice and TNF-alpha-deficient mice were significantly higher than that of wild-type mice. The present study using cytokine-gene knockout mice directly demonstrated that not only TNF-alpha but also IFN-gamma is involved in lethality of Stx1 and Stx2.
Sasaki
Sanae
S
Department of Bacteriology, Hirosaki University School of Medicine, Hirosaki, Japan.
Omoe
Katsuhiko
K
Tagawa
Yoh ichi
Yi
Iwakura
Yoichiro
Y
Sekikawa
Kenji
K
Shinagawa
Kunihiro
K
Nakane
Akio
A
D000818:Animals; D007371:Interferon-gamma / Q000032:analysis / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D012333:RNA, Messenger / Q000032:analysis; D022622:Shiga Toxin 1 / Q000633:toxicity*; D022641:Shiga Toxin 2 / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000172:deficiency / Q000502:physiology*
D012333:RNA, Messenger; D022622:Shiga Toxin 1; D022641:Shiga Toxin 2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma