title: KE-758, an active metabolite of the new anti-rheumatic drug KE-298, suppresses production of tumor necrosis factor-alpha and interleukin-1 beta in THP-1, a human monocyte cell line.
abstract: KE-758, an active metabolite of KE-298, is a novel sulfhydryl antirheumatic drug. We analyzed the effect of KE-758 on tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta production by a human monocytes cell line (THP-1 cells), stimulated with interferon-gamma (IFN-gamma) plus lipopolysaccharide (LPS). We compared the effects with other thiol-modifying antirheumatic drugs such as D-penicillamine, bucillamine and auranofin. THP-1 cells were treated with IFN-gamma for 16 h and were then exposed to LPS for an additional 6 h (for TNF-alpha detection) or 24 h (for IL-1 beta detection). The amounts of TNF-alpha and IL-1 beta in culture supernatants were measured using enzyme-linked immunosorbent assay. KE-758 and auranofin but not D-penicillamine and bucillamine significantly suppressed both TNF-alpha and IL-1 beta. Auranofin suppressed IL-1 beta production by reducing cellular viability. Reverse transcriptase-polymerase chain reaction analysis revealed that the suppressive effect of KE-758 is based on the inhibition of messenger ribonucleic acid expression of TNF-alpha and IL-1 beta. KE-758 had no effect on p75 and p55 soluble TNF receptor production in IFN-gamma and LPS-stimulated THP-1 cells. Thus, KE-758 inhibits both TNF-alpha and IL-1 beta production and its antirheumatic profile is apparently distinct from that of D-penicillamine, bucillamine and auranofin.
authors.affiliation: Department of Pharmacology, Pharmaceutical Research Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan. masanori.sugimoto@po.rd.taisho.co.jp
authors.forename: M
authors.initials: M
authors.lastname: Sugimoto
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: M
authors.initials: M
authors.lastname: Yamashita
authors.forename: K
authors.initials: K
authors.lastname: Takeshita
authors.forename: S
authors.initials: S
authors.lastname: Nakaike
mesh_terms: D018501:Antirheumatic Agents / Q000378:metabolism / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology; D002460:Cell Line; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010396:Penicillamine / Q000494:pharmacology; D010654:Phenylbutyrates / Q000378:metabolism / Q000494:pharmacology*; D010666:Phenylpropionates / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018501:Antirheumatic Agents; D007375:Interleukin-1; C102509:KE 758; D008070:Lipopolysaccharides; D010654:Phenylbutyrates; D010666:Phenylpropionates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D001310:Auranofin; D007371:Interferon-gamma; D010396:Penicillamine; D003545:Cysteine; C078547:esonarimod; C026535:bucillamine