The Microtubule-Targeting Agent Pretubulysin Impairs the Inflammatory Response in Endothelial Cells by a JNK-Dependent Deregulation of the Histone Acetyltransferase Brd4.

Autor: Primke TF; Institute of Pharmaceutical Biology, Goethe University Frankfurt, 60438 Frankfurt, Germany.; LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Goethe University Frankfurt, 60596 Frankfurt, Germany., Ingelfinger R; Institute of Pharmaceutical Biology, Goethe University Frankfurt, 60438 Frankfurt, Germany.; LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Goethe University Frankfurt, 60596 Frankfurt, Germany., Elewa MAF; Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60596 Frankfurt, Germany.; Biochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt., Macinkovic I; Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60596 Frankfurt, Germany., Weigert A; Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60596 Frankfurt, Germany., Fabritius MP; Department of Otorhinolaryngology, Walter Brendel Centre of Experimental Medicine, University Hospital, 81377 Munich, Germany.; Department of Radiology, University Hospital, University of Munich, 81377 Munich, Germany., Reichel CA; Department of Otorhinolaryngology, Walter Brendel Centre of Experimental Medicine, University Hospital, 81377 Munich, Germany., Ullrich A; Institute of Organic Chemistry, Saarland University, 66123 Saarbrücken, Germany., Kazmaier U; Institute of Organic Chemistry, Saarland University, 66123 Saarbrücken, Germany., Burgers LD; Institute of Pharmaceutical Biology, Goethe University Frankfurt, 60438 Frankfurt, Germany., Fürst R; Institute of Pharmaceutical Biology, Goethe University Frankfurt, 60438 Frankfurt, Germany.; LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Goethe University Frankfurt, 60596 Frankfurt, Germany.
Jazyk: angličtina
Zdroj: Cells [Cells] 2023 Aug 21; Vol. 12 (16). Date of Electronic Publication: 2023 Aug 21.
DOI: 10.3390/cells12162112
Abstrakt: The anti-inflammatory effects of depolymerizing microtubule-targeting agents on leukocytes are known for a long time, but the potential involvement of the vascular endothelium and the underlying mechanistic basis is still largely unclear. Using the recently synthesized depolymerizing microtubule-targeting agent pretubulysin, we investigated the anti-inflammatory potential of pretubulysin and other microtubule-targeting agents with respect to the TNF-induced leukocyte adhesion cascade in endothelial cells, to improve our understanding of the underlying biomolecular background. We found that treatment with pretubulysin reduces inflammation in vivo and in vitro via inhibition of the TNF-induced adhesion of leukocytes to the vascular endothelium by down-regulation of the pro-inflammatory cell adhesion molecules ICAM-1 and VCAM-1 in a JNK-dependent manner. The underlying mechanism includes JNK-induced deregulation and degradation of the histone acetyltransferase Bromodomain-containing protein 4. This study shows that depolymerizing microtubule-targeting agents, in addition to their established effects on leukocytes, also significantly decrease the inflammatory activation of vascular endothelial cells. These effects are not based on altered pro-inflammatory signaling cascades, but require deregulation of the capability of cells to enter constructive transcription for some genes, setting a baseline for further research on the prominent anti-inflammatory effects of depolymerizing microtubule-targeting agents.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje