A majority of mice with caspace-12 died from sepsis within the first 48 hours after onset, while 60 percent of the caspase-12 deficient mice survived. The deficient mice also showed a significantly lower number of bacterial colony-forming units per milliliter of blood, suggesting that more efficient bacterial clearance occurs in the absence of caspase-12.
Caspase-12 is also an inhibitor of caspase-1, a related enzyme involved in the inflammation process. Caspase-1 deficient mice are two-to-three times more susceptible to lethal Escherichia coli infection than normal mice. Consequently, the study said, sepsis resistance in caspase-12 deficient mice was most likely due to an initial hyper-production of cytokines that fight the infection.
"The resulting beneficial effect of cytokine hyper-production runs contrary to some of the current thinking in sepsis research," Ulevitch said. "The general thinking is that this initial cytokine 'storm' is harmful, and that belief has been the basis of a number of unsuccessful clinical studies. In our study, cells containing caspase-12 appear to weaken the activity of caspase-1 that is normally essential for bacterial clearance and sepsis survival."
In another finding, researchers showed that both mouse models had similar levels of stress-induced apoptosis or programmed cell death. While caspase-12 was previously thought to be a key mediator of endoplasmic reticulum apoptosis, the new study found that the presence or absence of caspase-12 had no effect on apoptotic sensitivity whatsoever.
Others authors of the study include Maya Saleh (currently with McGill University), Melissa K. Wolinski, Steve J. Bensinger, Patrick Fitzgerald, Nathalie Droin, Dougl
Source:Scripps Research Institute