A bis-malonic acid fullerene derivative significantly suppressed IL-33-induced IL-6 expression by inhibiting NF-κB activation

• Published in: International immunopharmacology 2016-11, Vol.40, p.254-264
• Main Authors: Funakoshi-Tago, Megumi, Miyagawa, Yurika, Ueda, Fumihito, Mashino, Tadahiko, Moriwaki, Yasuhiro, Tago, Kenji, Kasahara, Tadashi, Tamura, Hiroomi
• Format: Article
• Language: English
• Subjects: Acids; Activation; Animals; Anti-Inflammatory Agents - pharmacology; Bone marrow; Bone marrow-derived mast cells; Buckminsterfullerene; Cytokines; Cytokines - antagonists & inhibitors; Cytokines - genetics; Cytokines - metabolism; Degradation; Diseases; Fullerene; Fullerenes; Fullerenes - pharmacology; IL-33; IL-6; Immune system; Inflammatory diseases; Interleukin 1; Interleukin 6; JNK protein; Malonates - pharmacology; MAP Kinase Kinase 4 - metabolism; Mast cells; Mast Cells - drug effects; Mast Cells - metabolism; Medical treatment; Mice, Inbred C57BL; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB; Nuclear transport; p38 Mitogen-Activated Protein Kinases - metabolism; Pathogenesis; Translocation
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2016.08.031

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. •A bis-malonic acid fullerene derivative inhibits the IL-33-induced IL-6 expression.•A bis-malonic acid fullerene derivative inhibits the IL-33-induced NF-κB activation.•A bis-malonic acid fullerene derivative directly inhibits IKK activation. The inhibitory mechanism of IL-33signaling pathway by the bis-malonic acid fullerene derivative. [Display omitted]