Lamkanfi Mohamed, Moreira Lilian O, Makena Patrudu, Spierings Diana C J, Boyd Kelli, Murray Peter J, Green Douglas R, Kanneganti Thirumala-Devi
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Blood. 2009 Mar 19;113(12):2742-5. doi: 10.1182/blood-2008-09-178038. Epub 2009 Jan 23.
Extensive apoptosis of leukocytes during sepsis and endotoxic shock constitutes an important mechanism linked to the excessive mortality associated with these disorders. Caspase inhibitors confer protection from endotoxin-induced lymphocyte apoptosis and improve survival, but it is not clear which caspases mediate lipopolysaccharide (LPS)-induced lymphocyte apoptosis and mortality. We report here that the apoptotic executioner caspase-7 was activated in the splenocytes of LPS-injected mice, suggesting a role for caspase-7 in lymphocyte apoptosis. Indeed, caspase-7-deficient mice were resistant to LPS-induced lymphocyte apoptosis and were markedly protected from LPS-induced lethality independently of the excessive production of serum cytokines. These results reveal for the first time a nonredundant role for caspase-7 in vivo and identify caspase-7 inhibition as a component of the mechanism by which caspase inhibitors protect from endotoxin-induced mortality.
脓毒症和内毒素休克期间白细胞的广泛凋亡是与这些病症相关的高死亡率的重要机制。半胱天冬酶抑制剂可保护细胞免受内毒素诱导的淋巴细胞凋亡并提高存活率，但尚不清楚哪些半胱天冬酶介导脂多糖（LPS）诱导的淋巴细胞凋亡和死亡率。我们在此报告，凋亡执行半胱天冬酶-7在注射LPS的小鼠脾细胞中被激活，提示半胱天冬酶-7在淋巴细胞凋亡中起作用。事实上，缺乏半胱天冬酶-7的小鼠对LPS诱导的淋巴细胞凋亡具有抗性，并且独立于血清细胞因子的过量产生而显著免受LPS诱导的致死性。这些结果首次揭示了半胱天冬酶-7在体内的非冗余作用，并确定半胱天冬酶-7抑制是半胱天冬酶抑制剂保护免受内毒素诱导的死亡率的机制的一个组成部分。
