Rosmarinic acid as a downstream inhibitor of IKK-beta in TNF-alpha-induced upregulation of CCL11 and CCR3

Br J Pharmacol. 2006 Jun;148(3):366-75. doi: 10.1038/sj.bjp.0706728.

Abstract

1. Tumor necrosis factor (TNF)-alpha is known to induce the expression of CCL11 and CCR3 via the activation of NF-kappaB. CCL11 (eotaxin), the C-C chemokine, is a potent chemoattractant for eosinophils and Th2 lymphocytes, and CCR3 is the receptor for CCL11. 2. In order to determine the effects of rosmarinic acid on the TNF-alpha-induced upregulation of CCL11 and CCR3 in human dermal fibroblasts, we performed an enzyme-linked immunosorbent assay for CCL11 and a Western blot assay for CCR3. The TNF-alpha-induced expression of CCL11 and CCR3 genes was attenuated by rosmarinic acid. 3. In our NF-kappaB luciferase reporter system, TNF-alpha-induced NF-kappaB activation was observed to be reduced by rosmarinic acid. In accordance with this result, rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling. 4. Using the NF-kappaB luciferase reporter system, Western blot analysis, and IKK-beta activity assay, we determined that rosmarinic acid inhibits IKK-beta activity in NF-kappaB signaling, which upregulates the expression of CCL11 and CCR3. Additionally, TNF-alpha-induced secretion of soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 molecules was found to be attenuated by rosmarinic acid. 5. Our results show that rosmarinic acid inhibits the expression of CCL11 and CCR3 by suppressing the IKK-beta activity in NF-kappaB activation signaling. Further, these results suggest that rosmarinic acid might inhibit the expression of NF-kappaB promoter-related genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chemokine CCL11
  • Chemokines, CC / antagonists & inhibitors
  • Chemokines, CC / genetics*
  • Cinnamates / pharmacology*
  • Depsides / pharmacology*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • Mice
  • NIH 3T3 Cells
  • Phosphorylation / drug effects
  • Receptors, CCR2
  • Receptors, Chemokine / antagonists & inhibitors
  • Receptors, Chemokine / genetics*
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • CCL11 protein, human
  • CCR2 protein, human
  • Ccl11 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL11
  • Chemokines, CC
  • Cinnamates
  • Depsides
  • Receptors, CCR2
  • Receptors, Chemokine
  • Tumor Necrosis Factor-alpha
  • I-kappa B Kinase
  • rosmarinic acid