title: Fumaric acid attenuates the eotaxin-1 expression in TNF-α-stimulated fibroblasts by suppressing p38 MAPK-dependent NF-κB signaling.
abstract: Eotaxin-1 is a potent chemoattractant for eosinophils and a critical mediator during the development of eosinophilic inflammation. Fumaric acid is an intermediate product of the citric acid cycle, which is source of intracellular energy. Although fumaric acid ameliorates psoriasis and multiple sclerosis, its involvement in eotaxin-1-mediated effects has not been assessed. In this study, we investigated the effects of fumaric acid on eotaxin-1 expression in a mouse fibroblast cell line. We found that fumaric acid significantly inhibited tumor necrosis factor-α (TNF-α-induced eotaxin-1 expression. This fumaric acid effect was mediated through the inhibition of p38 mitogen-activated protein kinase (MAPK)-dependent nuclear factor (NF)-κB signaling. We also found that fumaric acid operates downstream of MEKK3 during TNF-α-induced NF-κB signaling, which upregulated eotaxin-1 expression. In addition, fumaric acid attenuated expression of CC-chemokine receptor 3 (CCR3), an eotaxin-1 receptor, and adhesion molecules that play important roles in eosinophil binding to induce allergic inflammation. Taken together, these findings indicate that inhibiting TNF-α-induced eotaxin-1 expression by fumaric acid occurs primarily through suppression of NF-κB signaling, which is mediated by inhibiting p38 MAPK and suggest that fumaric acid may be used as a complementary treatment option for eotaxin-1-mediated diseases.
authors.affiliation: Biospectrum Life Science Institute, Sangdaewon-Dong, Seongnam City, 442-13 Gyeonggi Do, Republic of Korea.
authors.forename: Kyung-Baeg
authors.initials: KB
authors.lastname: Roh
authors.forename: Eunsun
authors.initials: E
authors.lastname: Jung
authors.forename: Deokhoon
authors.initials: D
authors.lastname: Park
authors.forename: Jongsung
authors.initials: J
authors.lastname: Lee
mesh_terms: D000818:Animals; D054413:Chemokine CCL11 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005650:Fumarates / Q000494:pharmacology*; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D005650:Fumarates; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C032005:fumaric acid; D048051:p38 Mitogen-Activated Protein Kinases; D048748:MAP Kinase Kinase Kinase 3; C482626:Map3k3 protein, mouse
keywords: Eosinophils; Eotaxin-1; Fumaric acid; NF-κB; p38 MAPK