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      c-Myb Dominates TBK1-Mediated Endotoxin Tolerance in Kupffer Cells by Negatively Regulating DTX4


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          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- κB 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.

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          Most cited references31

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          NF-κB signaling in inflammation

          The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.
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            Endotoxin tolerance: new mechanisms, molecules and clinical significance.

            Prior exposure of innate immune cells like monocytes/macrophages to minute amounts of endotoxin cause them to become refractory to subsequent endotoxin challenge, a phenomenon called "endotoxin tolerance". Clinically, this state is associated with monocytes/macrophages in sepsis patients where they contribute to "immunosuppression" and mortality. The molecular mechanisms underlying endotoxin tolerance remain elusive. The recent appreciation of inflammation as a self-regulating process, the relative contribution of MyD88 versus TRIF signaling pathways in inducing activation or tolerance, plasticity of NF-kappaB function and the role of chromatin modification and microRNAs in LPS-induced gene reprogramming urges a re-evaluation of endotoxin tolerance. This review integrates these new findings into an up-to-date account of endotoxin tolerance, its molecular basis and clinical implications in different pathologies.
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              Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.

              To systematically investigate innate immune signaling networks regulating production of type I interferon, we analyzed protein complexes formed after microbial recognition. Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions; 21% of interactions were modulated by RNA, DNA, or LPS. Overexpression and depletion analyses identified 22 unique genes that regulated NF-κB and ISRE reporter activity, viral replication, or virus-induced interferon production. Detailed mechanistic analysis defined a role for mind bomb (MIB) E3 ligases in K63-linked ubiquitination of TBK1, a kinase that phosphorylates IRF transcription factors controlling interferon production. Mib genes selectively controlled responses to cytosolic RNA. MIB deficiency reduced antiviral activity, establishing the role of MIB proteins as positive regulators of antiviral responses. The HI5 provides a dynamic physical and regulatory network that serves as a resource for mechanistic analysis of innate immune signaling. Copyright © 2011 Elsevier Inc. All rights reserved.

                Author and article information

                J Immunol Res
                J Immunol Res
                Journal of Immunology Research
                31 March 2023
                : 2023
                : 5990156
                1Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
                2Department of Hepatobiliary Surgery, Chongqing University Three Gorges Hospital, Chongqing 404100, China
                Author notes

                Academic Editor: Peirong Jiao

                Author information
                Copyright © 2023 Yi-Lin Wu et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 28 February 2022
                : 11 January 2023
                : 14 February 2023
                Funded by: National Natural Science Foundation of China
                Award ID: 8197081191
                Award ID: 8180196
                Funded by: China Postdoctoral Science Foundation
                Award ID: 2019M653352
                Award ID: 2022MD723748
                Funded by: Basic Key Program of Chongqing University Three Gorges Hospital
                Award ID: 2022YJKYXM-002
                Research Article


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