Suppression of Inflammatory Responses by Handelin, a Guaianolide Dimer fromChrysanthemum boreale, via Downregulation of NF-κB Signaling and Pro-inflammatory Cytokine Production

Apr 3, 2014Journal of natural products

Handelin from Chrysanthemum boreale reduces inflammation by lowering NF-κB signaling and inflammatory molecules

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Abstract

Handelin (1) significantly inhibited acute inflammation in animal models.

Handelin reduced the production of nitric oxide and prostaglandin E2 in mouse macrophages stimulated by lipopolysaccharide.
The compound correlated with decreased expression of inducible nitric oxide synthase and cyclooxygenase-2 at both mRNA and protein levels.
Handelin suppressed the production of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, in LPS-stimulated macrophages.
The compound inhibited the activity of the nuclear factor-κB signaling pathway, which is involved in inflammation regulation.
Handelin also suppressed the activation of specific signaling proteins, ERK and JNK, associated with inflammatory responses.
In carrageenan and TPA-induced inflammation models, handelin reduced serum levels of interleukin-1β.

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The anti-inflammatory activity of handelin (1), a guaianolide dimer from Chrysanthemum boreale flowers, was evaluated in vivo, and the effects on mediators nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) and the nuclear factor-κB (NF-κB) and ERK/JNK signaling pathways were investigated in vitro. Compound 1 inhibited lipopolysaccharide (LPS)-induced production of NO and PGE2 in cultured mouse macrophage RAW 264.7 cells. The suppression of NO and PGE2 production by 1 was correlated with the downregulation of mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Compound 1 also suppressed the induction of pro-inflammatory cytokines TNF-α and IL-1β in LPS-stimulated RAW 264.7 cells. To further clarify the transcriptional regulatory pathway in the expression of iNOS and COX-2 by 1, the role of NF-κB was determined in RAW 264.7 cells. Compound 1 inhibits the binding activity of NF-κB into the nuclear proteins. The transcriptional activity of NF-κB stimulated with LPS was also suppressed by 1, which coincided with the inhibition of IκB degradation. Compound 1 also suppressed the activation of mitogen-activated protein kinases, including ERK and JNK signaling. In addition, the LPS-stimulated upregulation of miRNA-155 expression was suppressed by 1. The oral administration of 1 inhibited acute inflammation in carrageenan-induced paw and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear edema models. The serum level of IL-1β was also inhibited by 1 in a carrageenan-induced paw edema model. These findings suggest that the suppression of NF-κB activation and pro-inflammatory cytokine production may be a plausible mechanism of action for the anti-inflammatory activity of handelin.

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Suppression of Inflammatory Responses by Handelin, a Guaianolide Dimer fromChrysanthemum boreale, via Downregulation of NF-κB Signaling and Pro-inflammatory Cytokine Production

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