Scientists identify a septic shock susceptibility gene
In the November 15th issue of G&D, Dr. Robert Schneider and colleagues at NYU School of Medicine report that the AUF1 gene underlies susceptibility to septic shock.
Septic shock often follows a bacterial infection, and is characterized by the overwhelming release of pro-inflammatory cytokines by the body's immune system. This uncontrolled, systemic inflammatory response leads to dangerously low blood pressure and, ultimately, organ failure. One quarter to one half of sepsis patients die, making it the leading cause of hospital deaths in the US.
Dr. Schneider and colleagues demonstrate that the protein encoded by the AUF1 gene destabilizes the mRNA precursors of important pro-inflammatory cytokines. To better understand the role of AUF1 in septic shock, the scientists engineered a strain of transgenic mice deficient in the AUF1 gene, and then exposed them to bacterial endotoxin.
Dr. Schneider and colleagues observed that AUF1-deficinet mice were more sensitive to endotoxin-induced septic shock, displaying an exacerbated pro-inflammatory response and higher mortality rates. They found that AUF1 normally attenuates the immune response by limiting expression of two specific cytokines – TNFalpha and IL-1beta. In fact, treatment of AUF1-deficient mice with antibodies to neutralize TNFalpha and IL-1beta effectively combated endotoxic shock.
Further research is needed to delineate precisely how AUF1 regulates TNFalpha and IL-1beta, but Dr. Schneider is confident that "AUF1 is a key factor involved in septic shock, and its identification provides an important new target for development of agents to reduce mortality from this life-threatening condition."
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