Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states

被引：66

作者：

Adamson, Antony ^{[1
]}

Boddington, Christopher ^{[1
]}

Downton, Polly ^{[1
]}

Rowe, William ^{[1
]}

Bagnall, James ^{[1
]}

Lam, Connie ^{[1
]}

Maya-Mendoza, Apolinar ^{[2
]}

Schmidt, Lorraine ^{[1
]}

Harper, Claire V. ^{[1
]}

Spiller, David G. ^{[1
]}

Rand, David A. ^{[3
]}

Jackson, Dean A. ^{[1
]}

White, Michael R. H. ^{[1
]}

Paszek, Pawel ^{[1
]}

机构：

[1] Univ Manchester, Syst Microscopy Ctr, Fac Life Sci, Oxford Rd, Manchester M13 9PT, Lancs, England

[2] Danish Canc Soc, Res Ctr, Strandboulevarden 49, DK-2100 Copenhagen, Denmark

[3] Univ Warwick, Warwick Syst Biol & Math Inst, Coventry CV4 7AL, W Midlands, England

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;

关键词：

TEMPORAL CONTROL; DIGITAL ACTIVATION; NEGATIVE FEEDBACK; MESSENGER-RNA; TNF; RESPONSES; ALPHA; CELLS; TRANSCRIPTION; OSCILLATIONS;

D O I：

10.1038/ncomms12057

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Cells respond dynamically to pulsatile cytokine stimulation. Here we report that single, or well-spaced pulses of TNF alpha (> 100 min apart) give a high probability of NF-kappa B activation. However, fewer cells respond to shorter pulse intervals (<100 min) suggesting a heterogeneous refractory state. This refractory state is established in the signal transduction network downstream of TNFR and upstream of IKK, and depends on the level of the NF-kappa B system negative feedback protein A20. If a second pulse within the refractory phase is IL-1 beta instead of TNF alpha, all of the cells respond. This suggests a mechanism by which two cytokines can synergistically activate an inflammatory response. Gene expression analyses show strong correlation between the cellular dynamic response and NF-kappa B-dependent target gene activation. These data suggest that refractory states in the NF-kappa B system constitute an inherent design motif of the inflammatory response and we suggest that this may avoid harmful homogenous cellular activation.

引用

页数：14

共 70 条

[1]

Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription [J].