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

J Nat Prod. 2014 Apr 25;77(4):917-24. doi: 10.1021/np4009877. Epub 2014 Apr 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Chrysanthemum / chemistry*
  • Cyclooxygenase 2
  • Cytokines / metabolism*
  • Dinoprostone / metabolism
  • Down-Regulation
  • Edema / chemically induced
  • Edema / drug therapy
  • I-kappa B Proteins / drug effects
  • I-kappa B Proteins / 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
  • Nitric Oxide Synthase Type II / metabolism
  • Phytotherapy
  • Signal Transduction / drug effects
  • Terpenes / chemistry
  • Terpenes / pharmacology*
  • Tumor Necrosis Factor-alpha / drug effects

Substances

  • 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