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

Inulicin is one of the sesquiterpenes isolated from Inula japonica Thunb and its anti-inflammatory effect remains obscure. The current study aimed to demonstrate the anti-inflammatory activity along with the underlying mechanism of inulicin in lipopolysaccharide (LPS)-activated macrophages. Our data showed that inulicin significantly inhibited LPS-induced production of nitric oxide (NO), interleukin-6 (IL-6), c-c motif chemokine ligand2 (CCL2) and interleukin-1β (IL-1β) in RAW264.7 cells or mouse peritoneal macrophages (MPMs). At the transcriptional level, inulicin suppressed iNOS, IL-6, CCL2 and IL-1β mRNA levels in LPS-stimulated RAW264.7 cells. Further mechanism study indicated that it inhibited IκBα phosphorylation and prevented the nuclear translocation of p65, thereby inactivating nuclear factor-κB (NF-κB) signaling. Concurrently, inulicin also suppressed activator protein-1 (AP-1) signaling through reducing the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Moreover, in endotoxemia mice, a single intraperitoneal administration of inulicin also decreased the production of pro-inflammatory cytokines in serum and peritoneal lavage fluid. These findings suggest that inulicin might be a promising candidate for the treatment of inflammatory diseases.