Suppression of inflammatory responses by handelin, a guaianolide dimer from Chrysanthemum boreale, via downregulation of NF-κB signaling and pro-inflammatory cytokine production.

Abstract

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.

• Authors: Yuna Pyee, Hwa-Jin Chung, Tae Jun Choi, Hyen Joo Park, Ji-Young Hong, Ju Sun Kim, Sam Sik Kang, Sang Kook Lee
• Journal: Journal of natural products (J Nat Prod) Vol. 77 Issue 4 Pg. 917-24 (Apr 25 2014) ISSN: 1520-6025 [Electronic] United States
• PMID: 24689881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• I-kappa B Proteins
• Interleukin-1beta
• Lipopolysaccharides
• NF-kappa B
• NFKBIA protein, human
• Nfkbia protein, mouse
• Terpenes
• Tumor Necrosis Factor-alpha
• NF-KappaB Inhibitor alpha
• Nitric Oxide
• handelin
• Nitric Oxide Synthase Type II
• Cyclooxygenase 2
• PTGS2 protein, human
• Mitogen-Activated Protein Kinases
• Dinoprostone

Topics

• Animals
• Anti-Inflammatory Agents (chemistry, pharmacology)
• Chrysanthemum (chemistry)
• Cyclooxygenase 2
• Cytokines (metabolism)
• Dinoprostone (metabolism)
• Down-Regulation
• Edema (chemically induced, drug therapy)
• I-kappa B Proteins (drug effects, metabolism)
• Interleukin-1beta (drug effects)
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects)
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Animal
• Molecular Structure
• NF-KappaB Inhibitor alpha
• NF-kappa B (drug effects)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (drug effects, metabolism)
• Phytotherapy
• Signal Transduction (drug effects)
• Terpenes (chemistry, pharmacology)
• Tumor Necrosis Factor-alpha (drug effects)