1. Academic Validation
  2. Necroptosis promotes cell-autonomous activation of proinflammatory cytokine gene expression

Necroptosis promotes cell-autonomous activation of proinflammatory cytokine gene expression

  • Cell Death Dis. 2018 May 1;9(5):500. doi: 10.1038/s41419-018-0524-y.
Kezhou Zhu 1 2 Wei Liang 1 2 Zaijun Ma 1 2 Daichao Xu 3 Shuangyi Cao 1 Xiaojuan Lu 1 Nan Liu 1 Bing Shan 1 Lihui Qian 4 Junying Yuan 5 6
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Rd, PuDong District, 201203, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, 100049, Beijing, China.
  • 3 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA, 02115, USA.
  • 4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Rd, PuDong District, 201203, Shanghai, China. [email protected].
  • 5 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Rd, PuDong District, 201203, Shanghai, China. [email protected].
  • 6 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA, 02115, USA. [email protected].
Abstract

Necroptosis, a form of regulated necrotic cell death, is mediated by receptor interacting protein 1 (RIPK1), RIPK3, and Mixed Lineage Kinase domain-like protein (MLKL). However, the mechanism by which Necroptosis promotes inflammation is still unclear. Here we report that the expression of cytokines is robustly upregulated in a cell-autonomous manner during Necroptosis induced by tumor necrosis factor alpha (TNFα). We demonstrate that TNFα-induced Necroptosis leads to two waves of cytokine production. The first wave, more transient and weaker than the second, is in response to TNFα alone; whereas the second wave depends upon the necroptotic signaling. We show that Necroptosis promotes the transcription of TNFα-target genes in a cell-intrinsic manner. The activation of both NF-κB and p38 by the necroptotic machinery, RIPK1, RIPK3, and MLKL, is involved in mediating the robust induction of cytokine expression in the second wave. In contrast, Necroptosis induced by direct oligomerization of MLKL promotes cytokine production at much lower levels than that of Necroptosis induced with TNFα. Thus, we conclude that TNFα-induced Necroptosis signaling events mediated by RIPK1 and RIPK3 activation, in addition to the MLKL oligomerization, promotes the expression of cytokines involving multiple intracellular signaling mechanisms including NF-κB pathway and p38. These findings reveal that the necroptotic cell death machinery mounts an immune response by promoting cell-autonomous production of cytokines. Our study provides insights into the mechanism by which Necroptosis promotes inflammation in human diseases.

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