title: Rosmarinic acid as a downstream inhibitor of IKK-beta in TNF-alpha-induced upregulation of CCL11 and CCR3.
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.
authors.affiliation: Department of Skin cell biology, Biospectrum Life Science Institute (BLSI), SK Ventium 101-701, Dangjung Dong, Gunpo City, Kyunggi-do 436-776, Republic of Korea.
authors.forename: Jongsung
authors.initials: J
authors.lastname: Lee
authors.forename: Eunsun
authors.initials: E
authors.lastname: Jung
authors.forename: Youngji
authors.initials: Y
authors.lastname: Kim
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Lee
authors.forename: Junho
authors.initials: J
authors.lastname: Park
authors.forename: Seongtaek
authors.initials: S
authors.lastname: Hong
authors.forename: Chang-Gu
authors.initials: CG
authors.lastname: Hyun
authors.forename: Deokhoon
authors.initials: D
authors.lastname: Park
authors.forename: Yeong Shik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000235:genetics*; D002934:Cinnamates / Q000494:pharmacology*; D053630:Depsides / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000097123:Rosmarinic Acid
chemical_list: D054413:Chemokine CCL11; D019742:Chemokines, CC; D002934:Cinnamates; D053630:Depsides; D051550:I-kappa B Kinase; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D000097123:Rosmarinic Acid; C515456:CCL11 protein, human; C515334:CCR2 protein, human; C515457:Ccl11 protein, mouse; C515335:Ccr2 protein, mouse