Studies on biological activities of small molecules regulating the NF-κB signaling pathway induced by inflammatory cytokines

炎症性サイトカインによって誘導されるNF-κBシグナル伝達経路を制御する小分子化合物の生物活性に関する研究

2017-09-25

2017-09-25

The nuclear factor κB (NF-κB) signaling pathway plays a crucial role in our immune system. Small molecules with selective inhibitory activities are highly attractive agents to regulate NF-κB activation. Irciniastatin A is a pederin-type marine product that potently inhibits translation. In A549 cells, irciniastatin A induced a marked and sustained activation of extracellular signal-regulated kinase (ERK) and slightly induced the activation of p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK). Moreover, the TNF receptor 1 (TNF-R1) shedding induced by irciniastatin A was blocked by the ERK kinase inhibitor, neither by p38 MAP kinase inhibitor nor JNK inhibitor. In consequence, these results indicated that irciniastatin A is a unique translation inhibitor that induces a potent and sustained activation of the ERK pathway, and thereby promotes the ectodomain shedding of TNF receptor 1 in A549 cells. Previous research showed that eudesmane-type sesquiterpene lactones inhibited multiple steps of the canonical NF-κB signaling pathway. This study revealed that (11S)-2α-bromo-3-oxoeudesmano-12,6α-lactone, also known as santonin-related compound 2 (SRC2), not only blocked the LTβ-induced-NF-κB luciferase responsiveness but also restrained the nuclear translocation of NF-B subunits RelB and p52 without affecting the proteolytic processing of p100. Unlike (–)-dehydroxymethylepoxyquinomicin (DHMEQ), SRC2 inhibited the LTβ-induced nuclear translocation of both RelB wildtype and RelB (C144S) mutant whereas (–)-DHMEQ weakly inhibited the nuclear RelB (C144S). Furthermore, eudesmane-type sesquiterpenes lactones that possessed α-bromo ketones exerted stronger inhibitory activity than those compounds possessing a single α,β-unsaturated carbonyl moiety. Allantopyrone A-a natural compound synthesized from endophytic fungus, was found to induce the cross-linking of the components of TNF-R1 complex, including receptor-interacting protein 1 (RIP1), TNF receptor-associated factor 2 and inhibitor of NF-κB kinase β, and the NF-κB subunit RelA in A549 cells. The extracellular cysteine-rich domains of TNF-R1 were cross-linked by allantopyrone A more preferentially than its intracellular portion. This study showed that allantopyrone A interferes with multiple components of the TNF-R1 complex and blocks RIP1 modifications in the TNF-α-induced NF-κB signaling pathway.

博士（学術）

京都工芸繊維大学

14303甲第845号

http://hdl.handle.net/10212/2421

eng

ETD

Thesis or Dissertation

Thesis