The TNF family member 4-1BBL sustains inflammation by interacting with TLR signaling components during late-phase activation.
The TNF family member 4-1BBL sustains inflammation by interacting with TLR signaling components during late-phase activation.
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DOI：
10.1126/scisignal.2004431
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发表时间：
2013-10-01
影响因子：
7.3
通讯作者：
Kang YJ
中科院分区：
文献类型：
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作者：
Ma J;Bang BR;Lu J;Eun SY;Otsuka M;Croft M;Tobias P;Han J;Takeuchi O;Akira S;Karin M;Yagita H;Kang YJ
Toll样受体（TLR）依赖性信号传导的激活导致编码促炎因子（如肿瘤坏死因子α（TNF-α））的基因表达，并且该过程在炎症反应期间持续。TLR介导的炎症分两个阶段发生，依赖于TNF家族成员4-1BB配体（4-1BBL）在晚期信号传导期间维持TNF-α的产生。在这里，我们表明，Toll-白细胞介素-1受体（TIR）域的衔接蛋白（TIRAP）和IL-1 R相关激酶2（IRAK 2）需要通过与4-1BBL的相互作用来介导TLR 4反应的晚期。4-1bbl的表达依赖于早期TLR信号传导，该信号传导也诱导Tnf的表达，并且所产生的4-1BBL蛋白易位至质膜，在质膜处其与TLR物理相互作用以介导晚期次级TLR信号传导。TLR 4 -4- 1BBL介导的信号传导依赖于TIRAP和IRAK 2，以及由E3泛素连接酶TRAF 6、激酶TAK 1和衔接蛋白TAB 1组成的下游复合物，导致促分裂原活化蛋白激酶的刺激。早期TLR 4信号传导涉及由TLR 4、衔接蛋白MyD 88和TIRAP以及IRAK 2组成的信号传导复合物的形成，而由TLR 4、4-1BBL、TIRAP和IRAK 2组成的二级复合物的形成使晚期信号传导成为可能。抑制这一晚期途径可降低暴露于TLR 4配体脂多糖（LPS）的小鼠巨噬细胞产生TNF-α的程度，并改善LPS诱导的小鼠败血症。总之，这些数据表明TIRAP和IRAK 2对于由TLR-4-1BBL复合物的晚期信号传导介导的持续炎症反应至关重要。
Activation of Toll-like receptor (TLR)-dependent signaling leads to the expression of genes that encode pro-inflammatory factors, such as tumor necrosis factor α (TNF-α), and this process is sustained for the duration of the inflammatory response. TLR-mediated inflammation, which occurs in two phases, depends on the TNF family member 4-1BB ligand (4-1BBL) to sustain TNF-α production during late-phase signaling. Here, we showed that Toll–interleukin-1 receptor (TIR) domain–containing adaptor protein (TIRAP) and IL-1R–associated kinase 2 (IRAK2) were required to mediate the late phase of the TLR4 response through their interaction with 4-1BBL. Expression of 4-1bbl was dependent on early TLR signaling that also induced the expression of Tnf, and the resulting 4-1BBL protein translocated to the plasma membrane, where it physically interacted with TLRs to mediate late-phase, secondary TLR signaling. TLR4–4-1BBL–mediated signaling depended on TIRAP and IRAK2, as well as a downstream complex consisting of the E3 ubiquitin ligase TRAF6, the kinase TAK1, and the adaptor protein TAB1, leading to the stimulation of mitogen-activated protein kinases. Whereas early TLR4 signaling involved the formation of a signaling complex consisting of TLR4, the adaptor proteins MyD88 and TIRAP, and IRAK2, formation of a secondary complex consisting of TLR4, 4-1BBL, TIRAP, and IRAK2 enabled late-phase signaling. Inhibition of this late-phase pathway reduced the extent of TNF-α production by mouse macrophages exposed to the TLR4 ligand lipopolysaccharide (LPS), and ameliorated LPS-induced sepsis in mice. Together, these data suggest that TIRAP and IRAK2 are critical for the sustained inflammatory response that is mediated by late-phase signaling by the TLR–4-1BBL complex.
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影响因子：
64.8
作者：
Horng, T;Barton, GM;Medzhitov, R
通讯作者：
Medzhitov, R
DOI：
10.1073/pnas.0308496101
发表时间：
2004-03-09
影响因子：
11.1
作者：
Jiang, ZF;Mak, TW;Li, XX
通讯作者：
Li, XX
影响因子：
15.3
作者：
Kanakaraj, P;Schafer, PH;Fung-Leung, WP
通讯作者：
Fung-Leung, WP
DOI：
10.1073/pnas.0811273106
发表时间：
2009-06-23
影响因子：
11.1
作者：
Ferwerda, Bart;Alonso, Santos;Netea, Mihai G.
通讯作者：
Netea, Mihai G.
影响因子：
30.5
作者：
通讯作者：
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