The natural sesquiterpene lactone inulicin suppresses the production of pro-inflammatory mediators via inhibiting NF-κB and AP-1 pathways in LPS-activated macrophages

• Published in: Immunopharmacology and immunotoxicology Vol. 46; no. 5; p. 583
• Main Authors: Yan, Jingjing, Cai, Min, Zang, Chenchen, Li, Wenjing, Liu, Zhuangzhuang, Li, Ximeng, Gao, Yuan, Qi, Yun
• Format: Journal Article
• Language: English
• Published: England 01.10.2024
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Lactones - pharmacology; Lipopolysaccharides - pharmacology; Lipopolysaccharides - toxicity; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; NF-kappa B - metabolism; RAW 264.7 Cells; Sesquiterpenes - pharmacology; Signal Transduction - drug effects; Transcription Factor AP-1 - metabolism; NF-κB; Inulicin; JNK; endotoxemia; macrophage; anti-inflammation; AP-1; LPS; ERK
• ISSN: 1532-2513
• DOI: 10.1080/08923973.2024.2384899

Inulicin is a sesquiterpene lactone in Inulae Flos which is clinically used for the treatment of inflammatory diseases, such as cough, sputum production, and vomiting. This study aimed to demonstrate the anti-inflammatory activity and the underlying mechanism of inulicin by using lipopolysaccharide (LPS)-induced and models. LPS-stimulated RAW264.7 macrophages and mouse peritoneal macrophages (MPMs) were used for evaluating the anti-inflammatory activity of inulicin, while endotoxemia mice were used for evaluating its action. Cytokines' levels were determined by ELISA. RT-qPCR and western blot were used for assaying the mRNA and protein levels of target genes. RAW264.7 macrophages transfected with reporter plasmid pNFκB-TA-luc or pAP1-TA-luc were used for assaying the activation of NF-κB or AP-1 signaling. Inulicin significantly inhibited LPS-induced production of NO, IL-6, c-c motif chemokine ligand 2 (CCL2), and IL-1β in both RAW264.7 cells and MPMs. Mechanism study indicated that it could suppress inducible nitric oxide synthase, IL-6, CCL2, and IL-1β mRNA levels in LPS-stimulated RAW264.7 cells. Moreover, inulicin inhibited IκBα phosphorylation and prevented the nuclear translocation of p65, thereby inactivating NF-κB signaling. Concurrently, it also inhibited AP-1 signaling by reducing the phosphorylation of C-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). In endotoxemia mice, a single intraperitoneal administration of inulicin could decrease the production of pro-inflammatory cytokines in serum and peritoneal lavage fluid. The present study demonstrates that inulicin possesses anti-inflammatory effects and , which suggests that inulicin might be a promising candidate for the treatment of inflammatory diseases.