TNF phase III signalling in tolerant cells is tightly controlled by A20 and CYLD
TNF phase III signalling in tolerant cells is tightly controlled by A20 and CYLD
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DOI：
10.1016/j.cellsig.2017.06.009
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发表时间：
2017-09-01
影响因子：
4.8
通讯作者：
Brand, Korbinian
中科院分区：
文献类型：
--
作者：
Bikker, Rolf;Christmann, Martin;Brand, Korbinian
在炎症反应的急性期之后，必须严格控制炎症的消退。这一过程的失调导致炎症过度、慢性炎症性疾病或免疫瘫痪。不同的机制参与了炎症过程的协调终止，例如，炎症分子的表达和不同形式的耐受。为了更好地理解介导TNF依赖性炎症消退和诱导耐受的过程，有必要表征TNF长期（预）孵育期间的信号转导质量。在12至48小时的时间范围内，指定为TNF反应的第三阶段，我们测量了单核细胞中TNFR 1/NF-κ B依赖性通路的持续组成性激活。III期信号传导也被称为“TNF耐受细胞中的组成型信号传导”，其诱导包括A20的低敏感性和高敏感性靶基因的表达，A20由转录和蛋白水解事件差异调节。A20以Ia激酶复合物和部分RIP依赖性方式严格控制TNF长期组成性信号传导，该方式由佐剂ABIN 1支持。此外，CYLD蛋白参与调节这种晚期信号转导，而下游分子如Bc 13和p50不参与。A20和CYLD以不同的mRNA动力学表达，分别导致蛋白质水平的强烈或仅适度增加。有助于终止炎症的机制的鉴定将提供额外的诊断和治疗方面，以特异性地诊断炎症的某些方面并特异性地调节它们。
Following the acute phase of an inflammatory reaction, a strictly controlled resolution of inflammation is necessary. A dysregulation of this process leads to hyperinflammation, chronic inflammatory disease, or immune paralysis. Different mechanisms participate in the coordinated termination of the inflammatory process, e.g. the expression of antiinflammatory molecules and different forms of tolerance. To better understand the processes which mediate resolution of TNF-dependent inflammation and induce tolerance, it is necessary to characterize the signal transduction quality during TNF long-term (pre)incubation. Within a time frame from 12 to 48 h, designated as phase III of the TNF response, we measured an ongoing, constitutive activation of TNFR1/NF-kappa B-dependent pathways in monocytic cells. Phase III signalling which was also named "constitutive signaling in TNF tolerant cells" induces the expression of low-and high-sensitive target genes including A20 which is differentially regulated by transcriptional and proteolytic events. A20 strictly controls TNF long-term constitutive signalling in an la kinase complex-and partially RIP-dependent manner supported by adjuvant ABIN1. In addition, CYLD proteins participate in the regulation of this late-phase signal transduction, whereas downstream molecules such as Bc13 and p50 are not involved. A20 and CYLD are expressed with different mRNA kinetics resulting in a strong or only a modest increase in protein levels, respectively. The identification of mechanisms which contribute to the termination of inflammation will provide additional diagnostic and therapeutic aspects to specifically diagnose certain aspects of inflammation and specifically modulate them.