Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production
Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production
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DOI：
10.1038/cdd.2014.222
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发表时间：
2015-08-01
影响因子：
12.4
通讯作者：
Martin, S. J.
中科院分区：
文献类型：
--
作者：
Kearney, C. J.;Cullen, S. P.;Martin, S. J.
TNF通过抑制表达RIPK3的细胞中的caspase活性，促进一种被称为坏死下垂的受调节形式的坏死。由于坏死通常比细胞凋亡更具有促炎作用，因此人们普遍认为，tnf诱导的坏死性上睑下垂可能由于过度炎症而在体内有害。然而，由于TNF本质上是高度促炎的，由于其能够触发多种细胞因子和趋化因子的产生，坏死坏死导致的细胞快速死亡可能会减弱而不是增强TNF诱导的炎症。本研究表明，由于ripk3依赖性细胞死亡，tnf诱导的坏死下垂可有效抑制多种tnf诱导的促炎因子的产生。同样，坏死下垂也抑制lps诱导的促炎细胞因子的产生。与这些观察结果一致，来自tnf刺激细胞的上清液比来自tnf诱导的坏死细胞的上清液在体内更具有促炎作用。因此，坏死下垂减轻TNF-和lps驱动的炎症，这可能有利于细胞内病原体，通过抑制宿主免疫反应来唤起这种细胞死亡模式。
TNF promotes a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing RIPK3. Because necrosis is generally more pro-inflammatory than apoptosis, it is widely presumed that TNF-induced necroptosis may be detrimental in vivo due to excessive inflammation. However, because TNF is intrinsically highly pro-inflammatory, due to its ability to trigger the production of multiple cytokines and chemokines, rapid cell death via necroptosis may blunt rather than enhance TNF-induced inflammation. Here we show that TNF-induced necroptosis potently suppressed the production of multiple TNF-induced pro-inflammatory factors due to RIPK3-dependent cell death. Similarly, necroptosis also suppressed LPS-induced pro-inflammatory cytokine production. Consistent with these observations, supernatants from TNF-stimulated cells were more pro-inflammatory than those from TNF-induced necroptotic cells in vivo. Thus necroptosis attenuates TNF- and LPS-driven inflammation, which may benefit intracellular pathogens that evoke this mode of cell death by suppressing host immune responses.