Eudesmane-Type Sesquiterpene Lactones Inhibit Nuclear Translocation of the Nuclear Factor κB Subunit RelB in Response to a Lymphotoxin β Stimulation

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  • Quach Hue Tu
    Department of Applied Biology, Kyoto Institute of Technology
  • Kondo Tetsuya
    Department of Applied Biology, Kyoto Institute of Technology
  • Watanabe Megumi
    Department of Applied Biology, Kyoto Institute of Technology
  • Tamura Ryuichi
    Department of Applied Biology, Kyoto Institute of Technology
  • Yajima Yoshiki
    Department of Applied Biology, Kyoto Institute of Technology
  • Sayama Shinsei
    Department of Natural Sciences (Chemistry), Fukushima Medical University
  • Ando Masayoshi
    Department of Chemistry and Chemical Engineering, Niigata University
  • Kataoka Takao
    Department of Applied Biology, Kyoto Institute of Technology The Center for Advanced Insect Research Promotion (CAIRP), Kyoto Institute of Technology

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<p>The transcription factor nuclear factor κB (NF-κB) regulates various biological processes, including inflammatory responses. We previously reported that eudesmane-type sesquiterpene lactones inhibited multiple steps in the canonical NF-κB signaling pathway induced by tumor necrosis factor-α and interleukin-1α. In contrast, the biological activities of eudesmane-type sesquiterpene lactones on the non-canonical NF-κB signaling pathway remain unclear. In the present study, we found that (11S)-2α-bromo-3-oxoeudesmano-12,6α-lactone, designated santonin-related compound 2 (SRC2), inhibited NF-κB luciferase reporter activity induced by lymphotoxin β (LTβ) in human lung carcinoma A549 cells. Although SRC2 did not prevent the processing of the NF-κB subunit p100 induced by LTβ, it inhibited the nuclear translocation of RelB and p52 in response to the LTβ stimulation. In contrast to (−)-dehydroxymethylepoxyquinomicin, SRC2 inhibited the LTβ-induced nuclear translocation of the RelB (C144S) mutant in a manner similar to wild-type RelB. While eudesmane derivatives possessing an α-bromoketone moiety or α,β-unsaturated carbonyl moieties inhibited LTβ-induced NF-κB luciferase reporter activity, eudesmane derivatives possessing an α-bromoketone moiety exhibited stronger inhibitory activity on the LTβ-induced nuclear translocation of RelB than those possessing a single α-methylene-γ-lactone moiety. The results of the present study revealed that SRC2 inhibits the nuclear translocation of RelB in the non-canonical NF-κB signaling pathway induced by LTβ.</p>

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