Hotchkiss R S, Chang K C, Swanson P E, Tinsley K W, Hui J J, Klender P, Xanthoudakis S, Roy S, Black C, Grimm E, Aspiotis R, Han Y, Nicholson D W, Karl I E
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Nat Immunol. 2000 Dec;1(6):496-501. doi: 10.1038/82741.
Sepsis induces lymphocyte apoptosis and prevention of lymphocyte death may improve the chances of surviving this disorder. We compared the efficacy of a selective caspase-3 inhibitor to a polycaspase inhibitor and to caspase-3-/- mice. Both inhibitors prevented lymphocyte apoptosis and improved survival. Caspase-3-/- mice shared a decreased, but not total, block of apoptosis. The polycaspase inhibitor caused a very substantial decrease in bacteremia. Caspase inhibitors did not benefit RAG-1-/- mice, which had a > tenfold increase in bacteremia compared to controls. Adoptive transfer of T cells that overexpressed the anti-apoptotic protein Bcl-2 increased survival. T cells stimulated with anti-CD3 and anti-CD28 produced increased interleukin 2 and interferon gamma by 6 h. Thus, caspase inhibitors enhance immunity by preventing lymphocyte apoptosis and lymphocytes act rapidly, within 24 h, to control infection.
脓毒症会诱导淋巴细胞凋亡，而预防淋巴细胞死亡可能会提高在这种病症中存活的几率。我们比较了一种选择性半胱天冬酶-3抑制剂与一种多聚半胱天冬酶抑制剂以及半胱天冬酶-3基因敲除小鼠的疗效。两种抑制剂都能预防淋巴细胞凋亡并提高存活率。半胱天冬酶-3基因敲除小鼠的凋亡受到部分（而非完全）抑制。多聚半胱天冬酶抑制剂使菌血症显著降低。半胱天冬酶抑制剂对RAG-1基因敲除小鼠没有益处，与对照组相比，这些小鼠的菌血症增加了10倍以上。过表达抗凋亡蛋白Bcl-2的T细胞的过继转移提高了存活率。用抗CD3和抗CD28刺激的T细胞在6小时内产生的白细胞介素2和干扰素γ增加。因此，半胱天冬酶抑制剂通过预防淋巴细胞凋亡来增强免疫力，并且淋巴细胞在24小时内就能迅速发挥作用来控制感染。
