title: A bis-malonic acid fullerene derivative significantly suppressed IL-33-induced IL-6 expression by inhibiting NF-κB activation.
abstract: IL-33 functions as a ligand for ST2L, which is mainly expressed in immune cells, including mast cells. IL-33 is a potent inducer of pro-inflammatory cytokines, such as IL-6, and has been implicated in the pathogenesis of allergic inflammatory diseases. Therefore, IL-33 has recently been attracting attention as a new target for the treatment of inflammatory diseases. In the present study, we demonstrated that a water-soluble bis-malonic acid fullerene derivative (C60-dicyclopropane-1,1,1',1'-tetracarboxylic acid) markedly diminished the IL-33-induced expression of IL-6 in bone marrow-derived mast cells (BMMC). The bis-malonic acid fullerene derivative suppressed the canonical signaling steps required for NF-κB activation such as the degradation of IκBα and nuclear translocation of NF-κB by directly inhibiting the IL-33-induced IKK activation. Although p38 and JNK also contributed to IL-33-induced expression of IL-6, the bis-malonic acid fullerene derivative did not affect their activation. Furthermore, the bis-malonic acid fullerene derivative had no effect on the NF-κB activation pathway induced by TNFα and IL-1. These results suggest that the bis-malonic fullerene derivative has potential as a specific drug for the treatment of IL-33-induced inflammatory diseases by specifically inhibiting the NF-κB activation pathway.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. Electronic address: tago-mg@pha.keio.ac.jp.
authors.forename: Megumi
authors.initials: M
authors.lastname: Funakoshi-Tago
authors.affiliation: Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Yurika
authors.initials: Y
authors.lastname: Miyagawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Ueda
authors.affiliation: Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Mashino
authors.affiliation: Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Moriwaki
authors.affiliation: Division of Structural Biochemistry, Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken 329-0498, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tago
authors.affiliation: Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kasahara
authors.affiliation: Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Hiroomi
authors.initials: H
authors.lastname: Tamura
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D037741:Fullerenes / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008314:Malonates / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D037741:Fullerenes; D008314:Malonates; D016328:NF-kappa B; C030290:malonic acid; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: Bone marrow-derived mast cells; Fullerene; IL-33; IL-6; NF-κB