Anti-inflammatory activity of handelin through the modulation of NF-κB signaling and pro-inflammatory cytokine productions

Handelin, a guaianolide dimer, is a constituent of the flower of Chrysanthemum boreale Makino (Compositae). C. boreale have been used as traditional medicines for the treatment of vertigo and fever in Asian countries. The present study was designed to investigate the anti-inflammatory potential of handelin in vitro and in vivo. Handelin inhibited LPS-stimulated production of NO and PGE2 in cultured mouse macrophage RAW 264.7 cells. The suppression of NO and PGE2 production by handelin was correlated with the down-regulation of mRNA and protein expressions of iNOS and COX-2. Further study revealed that handelin suppressed the induction of pro-inflammatory cytokines including TNF-α and IL-1β as well as microRNA-155 in LPS-induced RAW264.7 cells. Activation of the transcriptional activity of NF-κB by LPS was also alleviated by handelin, which was well coincided with its inhibitory effect on IκB degradation. In addition, the activation of MAPKs such as ERK and JNK signaling was suppressed by handelin. In in vivo animal model, oral administration of handelin inhibited carrageenan-induced paw edema and TPA-induced ear edema, respectively. The analysis of cytokine production in serum showed that handelin dose-dependently inhibited the production of IL-1β in a carrageenan-induced paw edema. These findings suggest that handelin might be an active ingredient of C. boreale with the anti-inflammatory activity by inhibiting NF-κB activation and pro-inflammatory cytokine productions.