Torilin Inhibits Inflammation by Limiting TAK1-Mediated MAP Kinase and NF-κB Activation

Abstract

Torilin, a sesquiterpene isolated from the fruits of Torilis japonica, has shown antimicrobial, anticancer, and anti-inflammatory properties. However, data on the mechanism of torilin action against inflammation is limited. This study aimed at determining the anti-inflammatory property of torilin in LPS-induced inflammation using in vitro model of inflammation. We examined torilin's effect on expression levels of inflammatory mediators and cytokines in LPS-stimulated RAW 264.7 macrophages. The involvement of NF-kB and AP-1, MAP kinases, and adaptor proteins were assessed. Torilin strongly inhibited LPS-induced NO release, iNOS, PGE2, COX-2, NF-α, IL-1β, IL-6, and GM-CSF gene and protein expressions. In addition, MAPKs were also suppressed by torilin pretreatment. Involvement of ERK1/2, P38MAPK, and JNK1/2 was further confirmed by PD98059, SB203580, and SP600125 mediated suppression of iNOS and COX-2 proteins. Furthermore, torilin attenuated NF-kB and AP-1 translocation, DNA binding, and reporter gene transcription. Interestingly, torilin inhibited TAK1 kinase activation with the subsequent suppression of MAPK-mediated JNK, p38, ERK1/2, and AP-1 (ATF-2 and c-jun) activation and IKK-mediated I-κBα degradation, p65/p50 activation, and translocation. Together, the results revealed the suppression of NF-κB and AP-1 regulated inflammatory mediator and cytokine expressions, suggesting the test compound's potential as a candidate anti-inflammatory agent.

Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages

“…Similar to results seen in ROS-generation assays, the addition of TUG-891 to cells overexpressing these constructs did not further the effect (data not shown), suggesting that heightened receptor numbers yield maximal activity that is not sensitive to further agonism. In Raw 264.7 macrophages, LPS-induced phosphorylation of ERK1/2, can be activated in part by Ca 2+ -dependent signals through PI3-Kinase, phospholipase-C, or PKC activity (33–35), as well as via TAK1 scaffolds that are upheld by β-arrestin-2 (13,36–37). Hence, we next examined the effects of FFA4 isoform and C-terminal mutant expression on LPS-mediated ERK1/2 phosphorylation.…”

Enalapril attenuates endoplasmic reticulum stress and mitochondrial injury induced by myocardial infarction via activation of the TAK1/NFAT pathway in mice

“…Furthermore, the TAK1 inhibitor 5Z-7-oxozeanol abolished the decrease in infarct size observed in MDP-treated hearts (33). TAK1 regulates NF-κB signaling pathways that serve key roles in development, cell survival and immune responses (34). The evolutionarily conserved signaling intermediate in Toll pathways protein forms a signaling complex with TAK1 and TRAF6 through specific molecular interactions, where TAK1 may affect downstream cascade signaling for the activation of NF-κB (35).…”

Dentin-derived Inorganic Minerals Promote the Osteogenesis of Bone Marrow-derived Mesenchymal Stem Cells: Potential Applications for Bone Regeneration

“…In addition, extracellular calcium ions could bond the calcium-sensing receptors (CSR) to start the cascade reactions of the ERK MAPK pathway and induce the bone formation [42]. Calmodulin-dependent protein kinase II (CaMKII)/TAK1 could autophosphorylate in calcium mediated signal transduction system then activate p38 MAPK to induce cell activities [43,44]. In this study, the phosphorylation state of MAPK pathway was tested in BMMSCs when stimulated to differentiate by DIM and we found that ERK and p38 became phosphorylated.…”