TWEAK attenuates the transition from innate to adaptive immunity

被引:212
作者
Maecker, H
Varfolomeev, E
Kischkel, F
Lawrence, D
LeBlanc, H
Lee, W
Hurst, S
Danilenko, D
Li, J
Filvaroff, E
Yang, B
Daniel, D
Ashkenazi, A
机构
[1] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA
[2] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA
关键词
D O I
10.1016/j.cell.2005.09.022
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:931 / 944
页数:14
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