Limonin ameliorates dextran sulfate sodium-induced chronic colitis in mice by inhibiting PERK-ATF4-CHOP pathway of ER stress and NF-κB signaling

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammation regulated by intricate mechanisms. Limonin, a natural tetracyclic triterpenoid compound, possesses multiple bioactivities including anti-inflammation, anti-cancer and so on. However, the therapeutic potential and the underlying mechanism of limonin on IBD remain unclear. Here, we probe into the effect of limonin on chronic colitis induced by dextran sulfate sodium (DSS) and illustrated the potential mechanisms. We found that limonin relieved the risk and severity of DSS-induced chronic colitis in mice through various aspects including increasing body weight and colon length, decreasing the mortality rate, inhibiting MPO activity and improving colon pathology. Limonin also decreased the production of proinflammatory cytokines TNF-α, IL-1β, IL-6 and the expression of inflammatory proteins COX-2, iNOS in colon tissues from DSS-induced colitis mice. Moreover, limonin attenuated DSS-induced chronic colitis by inhibiting PERK-ATF4-CHOP pathway of endoplasmic reticulum (ER) stress and NF-κB signaling. In vitro, limonin not only decreased LPS-induced higher production of pro-inflammatory cytokines and inflammatory proteins mentioned above by inhibiting NF-κB signaling in macrophage cells RAW264.7, but also suppressed PERK-ATF4-CHOP pathway of ER stress. In summary, our study demonstrated that limonin mitigated DSS-induced chronic colitis via inhibiting PERK-ATF4-CHOP pathway of ER stress and NF-κB signaling. All of this study provides the possibility for limonin as an effective drug for chronic colitis of IBD in the future.