期刊
REDOX BIOLOGY
卷 8, 期 -, 页码 375-382出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.redox.2016.03.005
关键词
NF-kappa B; GSTP; S-glutathionylation; Asthma; Inflammation; Lung
资金
- National Institutes of Health [R01 HL060014, HL085464, HL085646]
- National Cancer Institute [CA85660]
- National Institute of General Medical Sciences [5P20GM103542]
Nuclear Factor kappa B (NF-kappa B) is a transcription factor family critical in the activation of pro- inflammatory responses. The NF-kappa B pathway is regulated by oxidant-induced post-translational modifications. Protein S-glutathionylation, or the conjugation of the antioxidant molecule, glutathione to reactive cysteines inhibits the activity of inhibitory kappa B kinase beta (IKK beta), among other NF-kappa B proteins. Glutathione S-transferase Pi (GSTP) is an enzyme that has been shown to catalyze protein S-glutathionylation (PSSG) under conditions of oxidative stress. The objective of the present study was to determine whether GSTP regulates NF-kappa B signaling, S-glutathionylation of IKK, and subsequent pro inflammatory signaling. We demonstrated that, in unstimulated cells, GSTP associated with the inhibitor of NF-kappa B, I kappa B alpha. However, exposure to LPS resulted in a rapid loss of association between I kappa B alpha and GSTP, and instead led to a protracted association between IKK beta and GSTP. LPS exposure also led to increases in the S-glutathionylation of IKK beta. SiRNA-mediated knockdown of GSTP decreased IKK beta-SSG, and enhanced NF-kappa B nuclear translocation, transcriptional activity, and pro-inflammatory cytokine production in response to lipopolysaccharide (LPS). TLK117, an isotype-selective inhibitor of GSTP, also enhanced LPS-induced NF-kappa B transcriptional activity and pro-inflammatory cytokine production, suggesting that the catalytic activity of GSTP is important in repressing NF-kappa B activation. Expression of both wild-type and catalytically-inactive Y7F mutant GSTP significantly attenuated LPS- or IKK beta-induced production of GM-CSF. These studies indicate a complex role for GSTP in modulating NF-kappa B, which may involve S-glutathionylation of IKK proteins, and interaction with NF-kappa B family members. Our findings suggest that targeting GSTP is a potential avenue for regulating the activity of this prominent pro-inflammatory and immunomodulatory transcription factor. (C) 2016 The Authors. Published by Elsevier B.V.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据