Narciclasine exerts anti‐inflammatory actions by blocking leukocyte–endothelial cell interactions and down‐regulation of the endothelial TNF receptor 1. Issue 8 (24th April 2019)

• Record Type: Journal Article
• Authors: Stark, Anna; Schwenk, Rebecca; Wack, Gesine; Zuchtriegel, Gabriele; Hatemler, Melissa G.; Bräutigam, Jacqueline; Schmidtko, Achim; Reichel, Christoph A.; Bischoff, Iris; Fürst, Robert
• Is Part Of: FASEB journal. Volume 33:Issue 8(2019)
• Page Start: 8771
• Page End: 8781
• Publication Date: 2019-04-24
• Subjects: inflammation -- vascular endothelial cells -- cell adhesion molecules -- nuclear factor‐κB; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201802440R
• Languages: English
• ISSNs: 0892-6638

Abstract

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 β and TGF‐β–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 antiinflammatory actions by blocking leukocyte–endothelial cell interactions and down‐regulation of the endothelial TNF receptor 1. FASEB J. 33, 8771–8781 (2019). www.fasebj.org