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.
Highlights
Inflammation is the body’s immediate response to tissue damage by pathogens or other stimuli
Upon LPS stimulation, TLR4 adaptor protein MyD88 recruits interleukin 1 receptor associated kinase 1 (IRAK1) and interleukin 1 receptor associated kinase 4 (IRAK4), resulting in recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6), and TRAF6 is activated by Lys63 (K63)-linked autoubiquitinated [6,7,8]
We demonstrated that P22077 exerts significant anti-inflammatory effects in vitro and in vivo through inhibition of the Nuclear factor κB (NF-κB) and MAPKs pathways via promoting K48-linked ubiquitination and degradation of TRAF6
Summary
Inflammation is the body’s immediate response to tissue damage by pathogens or other stimuli. Activated TRAF6 recruits and activates TGF-beta-activated www.aging-us.com kinase 1 (TAK1), TGF-beta activated kinase 1 binding protein 1 (TAB1), and TGF-beta activated kinase 1 binding protein 2 (TAB2) complex [9,10,11] This complex induces activation of IKKs complex (consists of the IKKα, IKKβ and IKKγ), the activated IKKs complex catalyzes IκBs phosphorylation and leads IκBs degradation in proteasome manner, resulting in p65 activation and induction of inflammatory cytokines production [12, 13]. We demonstrated that P22077 exerts significant anti-inflammatory effects in vitro and in vivo through inhibition of the NF-κB and MAPKs pathways via promoting K48-linked ubiquitination and degradation of TRAF6. These findings suggested that P22077 could be a promising agent for treatment inflammatory diseases
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