Department of Pathology, University of Massachusetts Medical School, Immunology and Microbiology Program, Worcester, MA 01605, USA.
Department of Pathology, University of Massachusetts Medical School, Immunology and Microbiology Program, Worcester, MA 01605, USA.
Cytokine Growth Factor Rev. 2014 Apr;25(2):167-74. doi: 10.1016/j.cytogfr.2013.12.013. Epub 2013 Dec 25.
It is now widely accepted that some forms of necrosis are controlled by a dedicated signaling pathway triggered by various cell surface and intracellular receptors. This regulated form of necrosis is mediated by the kinase activity of receptor-interacting protein kinase 1 (RIP1/RIPK1) and/or RIP3/RIPK3. A number of studies using the RIP1 kinase inhibitor Necrostatin-1 (Nec-1) and its derivatives, or RIP3-deficient mice demonstrated that RIP1 and RIP3 are involved in various infectious and sterile inflammatory diseases. As a consequence, these specific phenotypes were construed to depend on necrosis. However, emerging evidence indicates that the RIP1 kinase activity and RIP3 can also control apoptosis and inflammatory cytokine production independent of necrosis. Therefore, we may need to re-interpret conclusions drawn based on loss of RIP1 or RIP3 functions in in vivo models. We propose that studies of RIP1 and RIP3 in different inflammatory responses need to consider cell death-dependent and independent mechanisms of the RIP kinases.
现在人们普遍认为，某些形式的细胞坏死是由各种细胞表面和细胞内受体触发的专门信号通路所控制的。这种受调控的细胞坏死形式是由受体相互作用蛋白激酶 1（RIP1/RIPK1）和/或 RIP3/RIPK3 的激酶活性介导的。许多使用 RIP1 激酶抑制剂 Necrostatin-1（Nec-1）及其衍生物，或 RIP3 缺陷型小鼠的研究表明，RIP1 和 RIP3 参与了各种感染性和非感染性炎症性疾病。因此，这些特定的表型被认为依赖于坏死。然而，新出现的证据表明，RIP1 激酶活性和 RIP3 也可以独立于坏死来控制细胞凋亡和炎性细胞因子的产生。因此，我们可能需要重新解释基于体内模型中 RIP1 或 RIP3 功能丧失得出的结论。我们提出，在不同的炎症反应中研究 RIP1 和 RIP3 需要考虑 RIP 激酶的细胞死亡依赖和非依赖机制。
