Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
Department of Hepatobiliary Surgery, Chongqing University Three Gorges Hospital, Chongqing 404100, China.
J Immunol Res. 2023 Mar 31;2023:5990156. doi: 10.1155/2023/5990156. eCollection 2023.
As a protective mechanism regulating excessive inflammation, endotoxin tolerance plays a vital role in regulating endotoxin shock. Kupffer cells are players in mediating endotoxin tolerance. Nonetheless, the regulatory mechanism regulating endotoxin tolerance is barely known. A nonclassical IKK kinase called TRAF-associated NF-B activator (TANK)-binding kinase 1 (TBK1) can regulate inflammation. Here, we found that TBK1 is required for endotoxin tolerance in Kupffer cells. TBK1 plays a dominant role in regulating endotoxin tolerance by negatively regulating the induction of p100 processing. Deltex E3 ubiquitin ligase 4 (DTX4), a negative regulator of TBK1, can promote TBK1 K48-mediated ubiquitination and indirectly regulate endotoxin tolerance in Kupffer cells. We demonstrate that the c-Myb transcription factor could negatively regulate DTX4. Overexpression of c-Myb can be used to reduce the ubiquitination of TBK1 by reducing DTX4 transcription and to boost the anti-inflammatory effect of endotoxin tolerance. Thus, this study reveals a novel theory of TBK1-mediated endotoxin tolerance in Kupffer cells.
作为调节过度炎症的一种保护机制，内毒素耐受在调节内毒素休克方面起着至关重要的作用。Kupffer 细胞是介导内毒素耐受的参与者。然而，调节内毒素耐受的调控机制还知之甚少。一种非典型的 IKK 激酶，称为 TRAF 相关 NF-B 激活剂（TANK）结合激酶 1（TBK1），可以调节炎症。在这里，我们发现 TBK1 是 Kupffer 细胞内毒素耐受所必需的。TBK1 通过负调控 p100 加工的诱导，在调节内毒素耐受方面发挥主导作用。Deltex E3 泛素连接酶 4（DTX4）是 TBK1 的负调节剂，可促进 TBK1 K48 介导的泛素化，并间接调节 Kupffer 细胞中的内毒素耐受。我们证明 c-Myb 转录因子可以负调控 DTX4。c-Myb 的过表达可通过降低 DTX4 转录来减少 TBK1 的泛素化，并增强内毒素耐受的抗炎作用。因此，这项研究揭示了 Kupffer 细胞中 TBK1 介导的内毒素耐受的新理论。
