Santonin-related compound 2 inhibits the expression of ICAM-1 in response to IL-1 stimulation by blocking the signaling pathway upstream of IκB degradation

Kawai, Shigeto; Kataoka, Takao; Sugimoto, Hikaru; Nakamura, Akira; Kobayashi, Takafumi; Arao, Kei; Higuchi, Yohsuke; Ando, Masayoshi; Nagai, Kazuo

doi:10.1016/s0162-3109(00)00196-x

Cited by 29 publications

(29 citation statements)

References 13 publications

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“…79 We have also synthesized (11S)-2a-bromo-3-oxoeudesmano-13,6a-lactone (SRC2, as shown in Figure 4) from the starting material L-asantonin. 80 SRC2 is devoid of the a-methylene-g-lactone moiety, but has a bromoketone structure at the A-ring. SRC2 inhibits the induction of cell-surface ICAM-1 expression in response to IL-1 stimulation by blocking the signaling pathway upstream of IkB degradation.…”

Section: Thiol-reactive Ikk Inhibitorsmentioning

confidence: 99%

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Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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Pro-inflammatory cytokines, such as tumor necrosis factor-a and interleukin-1, trigger the signal transduction pathway leading to the activation of the transcription factor, nuclear factor-jB (NF-jB). NF-jB induces a large number of target genes involved in many biological processes, such as inflammation, immunity, cell survival, cell death and carcinogenesis. As therapeutic agents for inflammatory diseases and cancer, as well as bioprobes for the characterization of intracellular biological response and cell function, a large number of natural and synthetic small molecules have been identified to inhibit the activation of the NF-jB signaling pathway. This review focuses on recent progress in the identification and biological properties of small molecules targeting the NF-jB signaling pathway induced by pro-inflammatory cytokines.

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Section: Thiol-reactive Ikk Inhibitorsmentioning

confidence: 99%

“…SRC2 inhibits the induction of cell-surface ICAM-1 expression in response to IL-1 stimulation by blocking the signaling pathway upstream of IkB degradation. 80 Investigations of the molecular mechanism by which SRC2 inhibits NF-kB activation are in progress.…”

Section: Thiol-reactive Ikk Inhibitorsmentioning

confidence: 99%

Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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“…10) SRC2 inhibited multiple steps in the canonical NF-κB pathway induced by IL-1α and TNF-α. 11) In the present study, we found that SRC2 inhibited the non-canonical NF-κB signaling pathway induced by LTβ.…”

Section: Discussionmentioning

confidence: 98%

“…Reagents SRC2 (1), (11S)-3-oxoeudesmano-12,6α-lactone (2), 2α-bromo-3-oxoeudesm-11(13)-eno-12,6α-lactone (3), 3-oxoeudesm-11(13)-eno-12,6α-lactone (4), (11S)-3-oxoeudesm-1-eno-12,6α-lactone (5), (11S)-3β-hydroxyeudesm-1-eno-12,6α-lactone (6), tuberiferin (7), and 3β-hydroxyeudesma-1,11(13)-dieno-12,6α-lactone (8) were synthesized as described previously 10,11,13) (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

“…1), inhibited cell-surface intercellular adhesion molecule-1 (ICAM-1) expression induced by interleukin-1β (IL-1β) in human lung carcinoma A549 cells. 10) A structure-activity relationship study on eudesmane-type sesquiterpene lactones, including SRC2, showed that these sesquiterpene lactones inhibited multiple steps in the canonical NF-κB signaling pathway induced by TNF-α and IL-1α.…”

Section: )mentioning

confidence: 99%

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

Quach

Kondo

Watanabe

et al. 2017

Biological & Pharmaceutical Bulletin

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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.Key words eudesmane; lymphotoxin β; nuclear factor κB; RelB; sesquiterpene lactone Nuclear factor κB (NF-κB) is a family of structurally-related eukaryotic transcription factors that regulate the expression of a number of important genes, including those related to cell proliferation, cell death, and inflammation.1) The NF-κB family consists of five subunits: RelA(p65), RelB, c-Rel, p105/p50, and p100/p52. 2)Various types of stimuli, including inflammatory cytokines, activate the canonical and non-canonical NF-κB signaling pathways.3) In the canonical NF-κB pathway, tumor necrosis factor (TNF) family members, such as TNF-α, induce the activation of the inhibitor of NF-κB (IκB) kinase β. 4) In the cytosol, IκB sequesters the NF-κB heterodimers RelA and p50 and prevents their nuclear translocation. 4) Upon phosphorylation, IκB undergoes ubiquitination and proteasomal degradation, leading to the liberation and nuclear translocation of the RelA and p50 heterodimers. 5) In contrast, the non-canonical NF-κB pathway is triggered by other TNF family members, such as lymphotoxin β (LTβ).6) The NF-κB subunits RelB and p100/p52 play essential roles in the non-canonical NF-κB pathway. 7) In unstimulated cells, p100 constitutively associates with RelB in the cytosol and inhibits its activity.7) Upon a stimulation with LTβ, IκB kinase α is primarily activated and then directly phosphorylates p100.3) Phosphorylated p100 is ubiquitinated and processed into p52 by proteasome, leading to the nuclear ...

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