Narciclasine exerts anti-inflammatory actions by blocking leukocyte-endothelial cell interactions and down-regulation of the endothelial TNF receptor 1.
FASEB J
; 33(8): 8771-8781, 2019 08.
Article
in En
| MEDLINE
| ID: mdl-31017817
ABSTRACT
The alkaloid narciclasine has been characterized extensively as an anticancer compound. Accumulating evidence suggests that narciclasine has anti-inflammatory potential; however, the underlying mechanism remains poorly understood. We hypothesized that narciclasine affects the activation of endothelial cells (ECs), a hallmark of inflammatory processes, which is a prerequisite for leukocyte-EC interaction. Thus, we aimed to investigate narciclasine's action on this process in vivo and to analyze the underlying mechanisms in vitro. In a murine peritonitis model, narciclasine reduced leukocyte infiltration, proinflammatory cytokine expression, and inflammation-associated abdominal pain. Moreover, narciclasine decreased rolling and blocked adhesion and transmigration of leukocytes in vivo. In cultured ECs, narciclasine inhibited the expression of cell adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin and blocked crucial steps of the NF-κB activation cascade NF-κB promotor activity, p65 nuclear translocation, inhibitor of κB α (IκBα) phosphorylation and degradation, and IκBα kinase ß and TGF-ß-activated kinase 1 phosphorylation. Interestingly, these effects were based on the narciclasine-triggered loss of TNF receptor 1 (TNFR1). Our study highlights narciclasine as an interesting anti-inflammatory compound that effectively inhibits the interaction of leukocytes with ECs by blocking endothelial activation processes. Most importantly, we showed that the observed inhibitory action of narciclasine on TNF-triggered signaling pathways is based on the loss of TNFR1.-Stark, A., Schwenk, R., Wack, G., Zuchtriegel, G., Hatemler, M. G., Bräutigam, J., Schmidtko, A., Reichel, C. A., Bischoff, I., Fürst, R. Narciclasine exerts anti-inflammatory actions by blocking leukocyte-endothelial cell interactions and down-regulation of the endothelial TNF receptor 1.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenanthridines
/
Cell Adhesion
/
Amaryllidaceae Alkaloids
/
Receptors, Tumor Necrosis Factor, Type I
/
Human Umbilical Vein Endothelial Cells
/
Anti-Inflammatory Agents
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
FASEB J
Journal subject:
BIOLOGIA
/
FISIOLOGIA
Year:
2019
Type:
Article
Affiliation country:
Germany