P22077 inhibits LPS-induced inflammatory response by promoting K48-linked ubiquitination and degradation of TRAF6

Aging (Albany NY). 2020 Jun 9;12(11):10969-10982. doi: 10.18632/aging.103309. Epub 2020 Jun 9.

Abstract

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.

Keywords: P22077; inflammation; tumor necrosis factor receptor-associated factor 6; ubiquitin specific protease-7; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cyclooxygenase 2 / metabolism
  • Cytokines / metabolism
  • Female
  • Inflammation / drug therapy
  • Inflammation / etiology
  • Inflammation / metabolism*
  • Lipopolysaccharides / adverse effects
  • Lipopolysaccharides / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • RAW 264.7 Cells
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Thiophenes / pharmacology*
  • Ubiquitin-Specific Peptidase 7 / antagonists & inhibitors
  • Ubiquitination / drug effects*

Substances

  • 1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone
  • Anti-Inflammatory Agents
  • Cytokines
  • Lipopolysaccharides
  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • TRAF6 protein, mouse
  • Thiophenes
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Ubiquitin-Specific Peptidase 7