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Int J Mol Sci. 2017 Dec 4;18(12). pii: E2605. doi: 10.3390/ijms18122605.

Glycosaminoglycan-Mediated Downstream Signaling of CXCL8 Binding to Endothelial Cells.

Author information

1
Antagonis Biotherapeutics GmbH, Strasserhofweg 77a, 8045 Graz, Austria. rupert.derler@edu.uni-graz.at.
2
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Schubertstrasse 1, 8010 Graz, Austria. rupert.derler@edu.uni-graz.at.
3
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Schubertstrasse 1, 8010 Graz, Austria. bernd.gesslbauer@uni-graz.at.
4
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Schubertstrasse 1, 8010 Graz, Austria. corinna.weber@krages.at.
5
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Schubertstrasse 1, 8010 Graz, Austria. elisabeth.strutzmann@gmail.com.
6
Institute for Medical Biochemistry, University of Veterinary Medicine, Veterinärplatz 1, 1210 Vienna, Austria. ingrid.miller@vetmeduni.ac.at.
7
Antagonis Biotherapeutics GmbH, Strasserhofweg 77a, 8045 Graz, Austria. akungl@antagonis.com.
8
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Schubertstrasse 1, 8010 Graz, Austria. akungl@antagonis.com.

Abstract

The recruitment of leukocytes, mediated by endothelium bound chemokine gradients, is a vital process in inflammation. The highly negatively charged, unbranched polysaccharide family of glycosaminoglycans (GAGs), such as heparan sulfate and chondroitin sulfate mediate chemokine immobilization. Specifically the binding of CXCL8 (interleukin 8) to GAGs on endothelial cell surfaces is known to regulate neutrophil recruitment. Currently, it is not clear if binding of CXCL8 to GAGs leads to endothelial downstream signaling in addition to the typical CXCR1/CXCR2 (C-X-C motif chemokine receptor 1 and 2)-mediated signaling which activates neutrophils. Here we have investigated the changes in protein expression of human microvascular endothelial cells induced by CXCL8. Tumor necrosis factor alpha (TNFα) stimulation was used to mimic an inflammatory state which allowed us to identify syndecan-4 (SDC4) as the potential proteoglycan co-receptor of CXCL8 by gene array, real-time PCR and flow cytometry experiments. Enzymatic GAG depolymerization via heparinase III and chondroitinase ABC was used to emulate the effect of glycocalyx remodeling on CXCL8-induced endothelial downstream signaling. Proteomic analyses showed changes in the expression pattern of a number of endothelial proteins such as Zyxin and Caldesmon involved in cytoskeletal organization, cell adhesion and cell mobility. These results demonstrate for the first time a potential role of GAG-mediated endothelial downstream signaling in addition to the well-known CXCL8-CXCR1/CXCR2 signaling pathways in neutrophils.

KEYWORDS:

chondroitin sulphate; downstream; gene array; glycosaminoglycan; heparan sulphate; interleukin-8; proteomics; signaling

PMID:
29207576
PMCID:
PMC5751208
DOI:
10.3390/ijms18122605
[Indexed for MEDLINE]
Free PMC Article

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