Abstract
Adhesion molecules expressed on cerebral endothelial cells (ECs) mediate leukocyte recruitment and play a significant role in cerebral inflammation. Increased levels of adhesion molecules on the EC surface induce leukocyte infiltration into inflammatory areas and are thus hallmarkers of inflammation. Honokiol, isolated from the Chinese medicinal herb Magnolia officinalis, has various pharmacological activities, including anti-inflammatory effects, yet the nature of honokiol targeting molecules remains to be revealed. Here, we investigated the inhibitory effect of honokiol on neutrophil adhesion and vascular cell adhesion molecule-1 (VCAM-1) expression, which underlie its molecular target, and mechanisms for inactivating nuclear factor κ enhancer binding protein (NF-κB) in mouse cerebral ECs. Honokiol inhibited tumour necrosis factor-α (TNF-α)-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs. The inflammatory transcription factor NF-κB was downregulated by honokiol. Honokiol significantly blocked TNF-α–induced NF-κB p65 nuclear translocation and degradation of the proteasome-dependent inhibitor of NF-κB α (IκBα). From docking model prediction, honokiol directly targeted the ubiquitin–ubiquitin interface of Lys48-linked polychains. Moreover, honokiol prevented the TNF-α-induced Lys48-linked polyubiquitination, including IκBα-polyubiquitin interaction. Honokiol has protective anti-inflammatory effects on TNF-α-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs, at least in part by directly inhibiting ubiquitination-mediated IκBα degradation and then preventing NF-κB nuclear translocation.
Highlights
In endothelial cells (ECs) during central nervous system (CNS) inflammatory disorders such as stroke, multiple sclerosis, and brain tumor metastasis[3,9,10,11]
Honokiol targeted the ubiquitin–ubiquitin interface of K48-linked polychains, repressed the TNF-α–induced polyubiquitination of IκBα. Our study reveals another mechanism of honokiol in protecting ECs against inflammation by modulating the polyubiquitination of IκBαto fine-tune nuclear factor κenhancer binding protein (NF-κB)–activated transcriptional adaption, with potential as an agent for preventing and treating CNS diseases
The cell adhesion molecule VCAM-1 has a critical role in leucocyte adhesion to ECs at the site of CNS inflammation
Summary
In ECs during CNS inflammatory disorders such as stroke, multiple sclerosis, and brain tumor metastasis[3,9,10,11]. With TNF-αstimulation, the inhibitor of NF-κBα(IκBα)is phosphorylated and sequentially conjugated with K48-linked polyubiquitin, which leads to degradation of IκBαby the 26S proteasome Such degradation allows NF-κB to translocate into nucleus and sequentially stimulate the expression of pro-inflammatory target genes[15,16,17]. Honokiol is a potential natural product for treating CNS disorders, how it terminates NF-κB signalling downstream of the TNF receptor in inflammatory cerebral ECs is unknown. Honokiol targeted the ubiquitin–ubiquitin interface of K48-linked polychains, repressed the TNF-α–induced polyubiquitination of IκBα Our study reveals another mechanism of honokiol in protecting ECs against inflammation by modulating the polyubiquitination of IκBαto fine-tune NF-κB–activated transcriptional adaption, with potential as an agent for preventing and treating CNS diseases
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