(Homo-)harringtonine prevents endothelial inflammation through IRF-1 dependent downregulation of VCAM1 mRNA expression and inhibition of cell adhesion molecule protein biosynthesis

Burgers, Luisa D.; Ciurus, Sarah; Engel, Patrick; Kuntschar, Silvia; Raue, Rebecca; Kiprina, Anastasiia; Primke, Tobias; Schmid, Tobias; Weigert, Andreas; Schmidtko, Achim; Fürst, Robert (2024): (Homo-)harringtonine prevents endothelial inflammation through IRF-1 dependent downregulation of VCAM1 mRNA expression and inhibition of cell adhesion molecule protein biosynthesis. Biomedicine & Pharmacotherapy, 176: 116907. ISSN 07533322

Abstract

The plant alkaloid homoharringtonine (HHT) is a Food and Drug Administration (FDA)-approved drug for the treatment of hematologic malignancies. In addition to its well-established antitumor activity, accumulating evidence attributes anti-inflammatory effects to HHT, which have mainly been studied in leukocytes to date. However, a potential influence of HHT on inflammatory activation processes in endothelial cells, which are a key feature of inflammation and a prerequisite for the leukocyte-endothelial cell interaction and leukocyte extravasation, remains poorly understood. In this study, the anti-inflammatory potential of HHT and its derivative harringtonine (HT) on the TNF-induced leukocyte-endothelial cell interaction was assessed, and the underlying mechanistic basis of these effects was elucidated. HHT affected inflammation in vivo in a murine peritonitis model by reducing leukocyte infiltration and proinflammatory cytokine expression as well as ameliorating abdominal pain behavior. In vitro, HT and HHT impaired the leukocyte-endothelial cell interaction by decreasing the expression of the endothelial cell adhesion molecules intracellular adhesion molecule −1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). This effect was mediated by a bipartite mechanism. While HHT did not affect the prominent TNF-induced pro-inflammatory NF-ĸB signaling cascade, the compound downregulated the VCAM1 mRNA expression in an IRF-1-dependent manner and diminished active ICAM1 mRNA translation as determined by polysome profiling. This study highlights HHT as an anti-inflammatory compound that efficiently hampers the leukocyte-endothelial cell interaction by targeting endothelial activation processes.

• Doc-Type: Article (LMU)
• Organisational unit (Faculties): 18 Chemistry and Pharmacy > Department of Pharmacy
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 321115009
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892