TWEAK attenuates the transition from innate to adaptive immunity
TWEAK attenuates the transition from innate to adaptive immunity
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DOI：
10.1016/j.cell.2005.09.022
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发表时间：
2005-12-02
期刊：
影响因子：
64.5
通讯作者：
Ashkenazi, A
中科院分区：
文献类型：
--
作者：
Maecker, H;Varfolomeev, E;Ashkenazi, A
先天免疫是抵御感染的第一道防线，在适应性免疫的发展过程中保护宿主，并严重影响适应性反应的性质。我们发现，与肿瘤坏死因子 α (TNF-α) 相比，相关蛋白 TWEAK 减弱了从先天机制到适应性机制的转变。 TWEAK(-/-) 小鼠具有过多的自然杀伤 (NK) 细胞，并对细菌内毒素表现出超敏反应，其先天免疫细胞会产生过量的干扰素 (IFN)-γ 和白细胞介素 (IL)-12。 TWEAK 抑制转录激活因子 STAT-1 的刺激，并诱导 p65 核因子 (NF)-kappa B 与组蛋白脱乙酰酶 1 关联，从而抑制细胞因子的产生。 TWEAK(-/-) 小鼠在衰老时发育出超大的脾脏，具有扩大的记忆力和 T 辅助 1 (T(H)1) 亚型细胞，并针对肿瘤挑战产生更强的先天性和适应性 T(H)1 反应。因此，TWEAK 抑制 IFN-γ 和 IL-12 的产生，从而减少先天反应及其向适应性 T(H)1 免疫的转变。
Innate immunity is the first line of defense against infection, protecting the host during the development of adaptive immunity and critically affecting the nature of the adaptive response. We show that, in contrast to tumor necrosis factor alpha (TNF-alpha), the related protein TWEAK attenuates the transition from innate to adaptive mechanisms. TWEAK(-/-) mice had overabundant natural killer (NK) cells and displayed hypersensitivity to bacterial endotoxin, with their innate immune cells producing excess interferon (IFN)-gamma and interleukin (IL)-12. TWEAK inhibited stimulation of the transcriptional activator STAT-1 and induced p65 nuclear factor (NF)-kappa B association with histone deacetylase 1, repressing cytokine production. TWEAK(-/-) mice developed oversized spleens with expanded memory and T helper 1 (T(H)1) subtype cells upon aging and mounted stronger innate and adaptive T(H)1-based responses against tumor challenge. Thus, TWEAK suppresses production of IFN-gamma and IL-12, curtailing the innate response and its transition to adaptive T(H)1 immunity.