Research Paper Volume 12, Issue 11 pp 10969—10982
P22077 inhibits LPS-induced inflammatory response by promoting K48-linked ubiquitination and degradation of TRAF6
- 1 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Immunology, Shenzhen University School of Medicine, Shenzhen 518060, China
- 2 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310006, China
Received: January 9, 2020 Accepted: April 28, 2020 Published: June 9, 2020https://doi.org/10.18632/aging.103309
How to Cite
Copyright © 2020 Zhao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Inflammation is a biological process associated with multiple human disorders such as autoimmune diseases and metabolic diseases. Therefore, alleviation of inflammation is important for disease prevention or treatment. Recently, deubiquitinating enzymes (DUBs), especially ubiquitin specific protease-7 (USP7) attracts increasing attention as a potential drug target for inflammation. As an inhibitor of USP7, P22077 has been used to study the roles of USP7 in inflammatory response and neuroblastoma growth. However, the role and precise mechanism of P22077 in anti-inflammatory is still indistinct. In this study, we demonstrated that P22077 could attenuate the release of pro-inflammatory factors including TNF-α, IL-1β, IL-6 and NO, suppress mRNA expression of COX-2 and iNOS, and inhibit activation of NF-κB and MAPKs signaling pathways in Raw264.7 cells and mouse peritoneal macrophages after LPS stimulation. In vivo study showed that P22077 could relieve inflammatory response and reduce the lung injury in C57BL/6 mice with LPS-induced endotoxemia. Mechanically, P22077 might play an anti-inflammatory role by promoting tumor necrosis factor receptor-associated factor 6 (TRAF6) degradation via K48-linked polyubiquitination. These findings provide a rationale for the role of the P22077 in anti-inflammatory pathway and the promising clinical application of P22077 to treat inflammatory diseases.
LPS: lipopolysaccharide; TRAF6: tumor necrosis factor receptor-associated factor 6; USP7: ubiquitin specific protease-7; iNOS: inducible nitric oxide synthase; NO: nitrous oxide; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; IL-6: interleukin-6; NF-κB: Nuclear factor κB; DUBs: deubiquitinating enzymes.