Intracellular osteopontin negatively regulates toll-like receptor 4-mediated inflammatory response via regulating GSK3β and 4EBP1 phosphorylation. (August 2018)

• Record Type: Journal Article
• Authors: Yang, Haiou; Ye, Xingchen; Zhang, Xiaoqing; Li, Xiaoliang; Fu, Qihua; Tang, Zhenhua
• Is Part Of: Cytokine. Volume 108(2018)
• Page Start: 89
• Page End: 95
• Publication Date: 2018-08
• Subjects: Osteopontin -- Toll-like receptors -- Inflammation -- Negative regulation -- Immune response; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2018.03.013
• Languages: English
• ISSNs: 1043-4666

Abstract

Abstract: Toll-like receptors (TLRs) play an important role in host defense against invading pathogens. By initiating a signal transduction cascade, TLRs lead to the release of pro-inflammatory cytokines. However, the inappropriate activation of TLR signaling could result in inflammatory disorders or autoimmune diseases. Osteopontin (OPN) has been reported to be an inflammatory cytokine participating in cell-mediated immunity. However, the role of OPN in TLR-mediated immune responses is poorly understood. In the present study, OPN-deficient (OPN-/-) macrophages exhibited significantly higher levels of pro-inflammatory cytokines after stimulation with lipopolysaccharide (LPS). Our study also demonstrated that the intracellular OPN (iOPN) isoform acted as a negative regulator to inhibit LPS-induced inflammatory responses. Compared to WT macrophages, OPN-/- macrophages had lower Akt phosphorylation levels and higher GSK3β phosphorylation levels, which were downregulated by p-Akt. Moreover, as a down-stream target of Akt, 4EBP1 was hypo-phosphorylated in OPN-/- macrophages compared to 4EBP1 in WT macrophages. These findings reveal that iOPN can regulate GSK3β and 4EBP1 phosphorylation to inhibit TLR4-mediated inflammatory responses.