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Krishnathas, G. Melissa; Strödke, Benjamin; Mittmann, Laura; Zech, Thomas; Berger, Lena M.; Reichel, Christoph A.; Rösser, Silvia; Schmid, Tobias; Knapp, Stefan; Müller, Susanne; Bracher, Franz; Fürst, Robert and Bischoff-Kont, Iris (2021): C81-evoked inhibition of the TNFR1-NF kappa B pathway during inflammatory processes for stabilization of the impaired vascular endothelial barrier for leukocytes. In: Faseb Journal, Vol. 35, No. 6, e21656

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Chronic inflammation-related diseases are characterized by persistent leukocyte infiltration into the underlying tissue. The vascular endothelium plays a major role in this pathophysiological condition. Only few therapeutic strategies focus on the vascular endothelium as a major target for an anti-inflammatory approach. In this study, we present the natural compound-derived carbazole derivative C81 as chemical modulator interfering with leukocyte-endothelial cell interactions. An in vivo assay employing intravital microscopy to monitor leukocyte trafficking after C81 treatment in postcapillary venules of a murine cremaster muscle was performed. Moreover, in vitro assays using HUVECs and monocytes were implemented. The impact of C81 on cell adhesion molecules and the NF kappa B signaling cascade was analyzed in vitro in endothelial cells. Effects of C81 on protein translation were determined by incorporation of a puromycin analog-based approach and polysome profiling. We found that C81 significantly reduced TNF-activated leukocyte trafficking in postcapillary venules. Similar results were obtained in vitro when C81 reduced leukocyte-endothelial cell interactions by down-regulating cell adhesion molecules. Focusing on the NF kappa B signaling cascade, we found that C81 reduced the activation on multiple levels of the cascade through promoted I kappa B alpha recovery by attenuation of I kappa B alpha ubiquitination and through reduced protein levels of TNFR1 caused by protein translation inhibition. We suggest that C81 might represent a promising lead compound for interfering with inflammation-related processes in endothelial cells by down-regulation of I kappa B alpha ubiquitination on the one hand and inhibition of translation on the other hand without exerting cytotoxic effects.

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