Echinacea alkylamides modulate TNF-alpha gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways

FEBS Lett. 2004 Nov 19;577(3):563-9. doi: 10.1016/j.febslet.2004.10.064.


Echinacea plant preparations are widely used in the prevention and treatment of common cold. However, so far no molecular mechanism of action has been proposed. We analyzed the standardized tincture Echinaforce and found that it induced de novo synthesis of tumor necrosis factor alpha (TNF-alpha) mRNA in primary human monocytes/macrophages, but not TNF-alpha protein. Moreover, LPS-stimulated TNF-alpha protein was potently inhibited in the early phase but prolonged in the late phase. A study of the main constituents of the extract showed that the alkylamides dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides (1/2), trienoic (3) and dienoic acid (4) derivatives are responsible for this effect. The upregulation of TNF-alpha mRNA was found to be mediated by CB2 receptors, increased cAMP, p38/MAPK and JNK signaling, as well as NF-kappaB and ATF-2/CREB-1 activation. This study is the first to report a possible molecular mechanism of action of Echinacea, highlighting the role of alkylamides as potent immunomodulators and potential ligands for CB2 receptors.

MeSH terms

  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Echinacea*
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression Regulation / drug effects*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Kinetics
  • Leukocytes, Mononuclear / drug effects
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Molecular Structure
  • NF-kappa B / metabolism
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology*
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Lipopolysaccharides
  • NF-kappa B
  • Plant Extracts
  • RNA, Messenger
  • Receptor, Cannabinoid, CB2
  • Tumor Necrosis Factor-alpha
  • Cyclic AMP
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases