title: Stimulation of pro-inflammatory responses by mebendazole in human monocytic THP-1 cells through an ERK signaling pathway.
abstract: Oral helminthic mebendazole (MBZ) has been reported to cause liver injury with inflammatory responses. However, the underlying mechanism remains unknown. To examine the inflammatory reactions, we investigated whether MBZ and other helminthic drugs increase the release of pro-inflammatory cytokines and chemokines using human monocytic cells. The release of interleukin (IL)-8 and tumor necrosis factor (TNF) α from human monocytic THP-1 cells was significantly increased by treatment with MBZ, albendazole (ABZ), fenbendazole (FBZ), or oxibendazole (OBZ), but not by albendazole sulfoxide or praziquantel, suggesting that MBZ and structurally similar drugs can stimulate monocytes and increase the release of pro-inflammatory cytokines. MBZ also significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 in THP-1 cells. Pretreatment with the MAP kinase/ERK kinase 1/2 inhibitor U0126 significantly suppressed the increase of IL-8 and TNFα levels by MBZ, ABZ, FBZ, or OBZ treatment in THP-1 cells, but the p38 mitogen-activated protein kinase inhibitor SB203580 or JNK1/2 inhibitor SP600125 did not. These results suggested that an ERK1/2 pathway plays an important role in the release of IL-8 and TNFα in THP-1 cells treated with MBZ and structurally similar drugs. In conclusion, the release of inflammatory mediators by MBZ might be one of the mechanisms underlying immune-mediated liver injury. This in vitro method may be useful to predict adverse inflammatory reactions that lead to hepatotoxicity.
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mizuno
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D000969:Antinematodal Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D008463:Mebendazole / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000873:Anthracenes; D000969:Antinematodal Agents; D018925:Chemokines; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016209:Interleukin-8; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D008463:Mebendazole; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580