Narciclasine exerts anti-inflammatory actions by blocking leukocyte-endothelial cell interactions and down-regulation of the endothelial TNF receptor 1

Stark, Anna; Schwenk, Rebecca; Wack, Gesine; Zuchtriegel, Gabriele; Hatemler, Melissa G.; Braeutigam, Jacqueline; Schmidtko, Achim; Reichel, Christoph A.; Bischoff, Iris und Fuerst, Robert (2019): Narciclasine exerts anti-inflammatory actions by blocking leukocyte-endothelial cell interactions and down-regulation of the endothelial TNF receptor 1. In: Faseb Journal, Bd. 33, Nr. 8: S. 8771-8781

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-kappa B activation cascade: NF-kappa B promotor activity, p65 nuclear translocation, inhibitor of kappa B alpha (I kappa B alpha) phosphorylation and degradation, and I kappa B alpha kinase beta and TGF-beta-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., Brautigam, J., Schmidtko, A., Reichel, C. A., Bischoff, I., Furst, R. Narciclasine exerts anti-inflammatory actions by blocking leukocyte-endothelial cell interactions and down-regulation of the endothelial TNF receptor 1.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0892-6638
• Sprache: Englisch