Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis
Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis
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DOI：
10.1073/pnas.1031788100
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发表时间：
2003-05-27
影响因子：
11.1
通讯作者：
Karl, IE
中科院分区：
文献类型：
--
作者：
Hotchkiss, RS;Chang, KC;Karl, IE
在脓毒症中，可发生坏死性和凋亡性细胞死亡。凋亡细胞诱导无能，可能会损害宿主的反应，而坏死细胞引起免疫激活，可能会导致增强抗菌防御。我们确定了在临床相关的脓毒症模型中，凋亡或坏死细胞的过继转移是否影响存活率。我们还评估了过继转移凋亡或坏死细胞对原型TH 1和TH 2细胞因子IFN-γ和IL-4的影响。C57 BL 6/J小鼠具有凋亡（辐射）或坏死（冻融）脾细胞的过继转移。对照组接受生理盐水。凋亡细胞显著增加死亡率，而坏死脾细胞显著提高存活率，P <或等于0.05。凋亡或坏死细胞对存活率的对比效应分别反映为对脾细胞IFN-γ产生的相反效应，产生分别大大减少和增加。重要的是，施用抗IFN-γ抗体或使用IFN-γ敲除小鼠阻止了坏死细胞发生的存活益处。这项研究表明，细胞死亡的类型影响临床相关模型中的存活率，并确定了免疫抑制的机制，这是脓毒症的标志。坏死细胞（和可能的凋亡细胞）通过IFN-γ的调节发挥其作用。
In sepsis, both necrotic and apoptotic cell death can occur. Apoptotic cells induce anergy that could impair the host response, whereas necrotic cells cause immune activation that might result in enhanced antimicrobial defenses. We determined whether adoptive transfer of apoptotic or necrotic cells impacted survival in a clinically relevant sepsis model. We also evaluated the effects of adoptive transfer of apoptotic or necrotic cells on the prototypical TH1 and TH2 cytokines IFN-gamma and IL-4, respectively. C57BL6/J mice had adoptive transfer of apoptotic (irradiated) or necrotic (freeze thaw) splenocytes. Controls received saline. Apoptotic cells greatly increased mortality, whereas necrotic splenocytes markedly improved survival, P less than or equal to 0.05. The contrasting effects that apoptotic or necrotic cells exerted on survival were mirrored by opposite effects on splenocyte IFN-gamma production with greatly decreased and increased production, respectively. Importantly, either administration of anti-IFN-gamma antibodies or use of IFN-gamma knockout mice prevented the survival benefit occurring with necrotic cells. This study demonstrates that the type of cell death impacts survival in a clinically relevant model and identifies a mechanism for the immune suppression that is a hallmark of sepsis. Necrotic cells (and likely apoptotic cells) exert their effects via modulation of IFN-gamma.