Rhein attenuates lipopolysaccharide-primed inflammation through NF-κB inhibition in RAW264.7 cells: targeting the PPAR-γ signal pathway

• Published in: Canadian journal of physiology and pharmacology 2020-06, Vol.98 (6), p.357-365
• Main Authors: Wen, Quan, Miao, Jifei, Lau, Ngaikeung, Zhang, Chaoying, Ye, Peng, Du, Shaohui, Mei, Liyan, Weng, Huandi, Xu, Qin, Liu, Xia, Chen, Dongfeng, Zhang, Fengxue, Li, Chun, Li, Hui
• Format: Article
• Language: English
• Subjects: Animals; Anthraquinones - pharmacology; Anthraquinones - therapeutic use; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Cell Survival - drug effects; cellules RAW264.7; Gene Expression Regulation - drug effects; Histone deacetylase; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; lipopolysaccharide; Lipopolysaccharides; Lipopolysaccharides - pharmacology; LPS; Mice; NF-kappa B - antagonists & inhibitors; NF-κB; NF-κB protein; Nitric-oxide synthase; Peroxisome proliferator-activated receptors; PPAR gamma - metabolism; PPAR-γ; RAW 264.7 Cells; RAW264.7 cells; rhein; rhéine; Rosiglitazone; Sepsis; Signal transduction; Signal Transduction - drug effects; Tumor necrosis factor-α
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2019-0389

Inflammation is a common inducer of numerous severe diseases such as sepsis. The NF-κB signaling pathway plays a key role in the inflammatory process. Its activation promotes the release of pro-inflammatory mediators like inducible nitric oxide synthase and tumor necrosis factor alpha. Peroxisome proliferator-activated receptor gamma (PPAR-γ) inactivates nuclear factor kappa B (NF-κB) and subsequently attenuates inflammation. Rhein, an agent isolated from rhubarb, has been known to have anti-inflammatory effects. However, its influence on PPAR-γ remains largely unknown. In this study, an inflammation model was constructed by stimulating RAW264.7 cells with lipopolysaccharide. Rhein was used as a therapeutic agent, while rosiglitazone (PPAR-γ activator) and GW9662 (PPAR-γ inhibitor) were used as disrupters for in depth studies. The results demonstrated that rhein inhibits NF-κB activation and inflammatory factor release. However, GW9662 significantly reduced this effect, indicating that PPAR-γ is a critical mediator in the rhein-mediated anti-inflammatory process. Additionally, positive modulation of PPAR-γ expression and activity by rosiglitazone correspondingly influenced the effects of rhein on inflammatory factors and NF-κB expression. We also found that rhein could enhance PPAR-γ, NF-κB, and histone deacetylase 3 (HDAC3) binding. These results indicate that rhein exerts its anti-inflammation function by regulating the PPAR-γ–NF-κB–HDAC3 axis.