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Abstract
<p class="first" id="d1180929e156">Fisetin (3,7,3',4'-tetrahydroxyflavone), a natural
flavonoid, is a therapeutic agent
for respiratory inflammatory diseases such as chronic obstructive pulmonary disease
(COPD). However, detailed molecular mechanisms regarding the target protein of fisetin
remain unknown. Fisetin significantly reduces tumour necrosis factor alpha (TNF-α)-induced
interleukin (IL)-8 levels by inhibiting both nuclear factor kappa B (NF-κB) transcriptional
activity and the phosphorylation of its upstream effectors. We show that fisetin prevents
interactions between protein kinase C (PKC)δ and TNF receptor-associated factor 2
(TRAF2), thereby inhibiting the inhibitor of kappa B kinase (IKK)/NF-κB downstream
signalling cascade. Furthermore, we found that fisetin directly binds to PKCδ in vitro.
Our findings provide evidence that fisetin inhibits the TNF-α-activated IKK/NF-κB
cascade by targeting PKCδ, thereby mediating inflammatory diseases such as COPD. These
data suggest that fisetin is a good therapeutic drug for the treatment of inflammatory
lung diseases, such as COPD, by inhibiting the TNF-α/NF-κB signalling pathway.
</p>