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Fractalkine upregulates intercellular adhesion molecule-1 in endothelial cells through CX3CR1 and the Jak Stat5 pathway
Journal article   Open access   Peer reviewed

Fractalkine upregulates intercellular adhesion molecule-1 in endothelial cells through CX3CR1 and the Jak Stat5 pathway

Xiao Ping Yang, Subhendra Mattagajasingh, Shaobo Su, Guibin Chen, Zheqing Cai, Karen Fox-Talbot, Kaikobad Irani and Lewis C Becker
Circulation research, Vol.101(10), pp.1001-1008
11/09/2007
DOI: 10.1161/CIRCRESAHA.107.160812
PMID: 17885215
url
https://doi.org/10.1161/CIRCRESAHA.107.160812View
Published (Version of record) Open Access

Abstract

Fractalkine (FKN) is a membrane-bound chemokine that can be released by proteolysis to produce soluble FKN (s-FKN). FKN and its receptor, CX3CR1, are believed to be important factors in atherosclerosis and may play a role in acute inflammatory responses. Although FKN is expressed on endothelial cells (ECs), CX3CR1 is reported to reside mainly on certain leukocyte populations. RT-PCR and Western blotting demonstrated that both human coronary artery and umbilical vein ECs expressed CX3CR1 mRNA and protein. Confocal microscopy showed that CX3CR1 was located at the cell membrane and to a lesser extent in the cytoplasm. Following exposure of both types of ECs to hypoxia and reoxygenation, FKN expression increased rapidly and s-FKN was shed into the culture medium. The addition of s-FKN protein to cultured ECs resulted in a dose-dependent increase in intercellular adhesion molecule (ICAM)-1 mRNA. Perfusion of mouse hearts with s-FKN protein increased expression of ICAM-1 protein in vascular endothelium. Transfection of ECs with CX3CR1-interfering RNA to knockdown the receptor resulted in decreased ICAM-1 expression after s-FKN stimulation. In addition, when ECs were stimulated with s-FKN, greater adhesion of human neutrophils to the ECs was observed. This increase was ICAM-1 dependent and was blocked by CX3CR1 knockdown. Following exposure to s-FKN, ECs exhibited increased phosphorylation of Jak2 and Stat5 and the ICAM-1 expression induced by s-FKN was blocked by silencing of Stat5 with small interfering RNA. Vascular ECs express both FKN and its receptor CX3CR1. s-FKN is shed from ECs following hypoxia/reoxygenation and acts through CX3CR1 on ECs to increase ICAM-1 expression and promote neutrophil adhesion through activation of the Jak-Stat5 pathway.
 Endothelium, Vascular - cytology Neutrophils - cytology Chemokine CX3CL1 - metabolism Humans Male Hypoxia - metabolism Chemokine CX3CL1 - pharmacology STAT5 Transcription Factor - genetics STAT5 Transcription Factor - metabolism RNA Interference Janus Kinase 2 - metabolism Up-Regulation - physiology Receptors, Chemokine - genetics Umbilical Veins - cytology Endothelium, Vascular - immunology Mice, Inbred C57BL Receptors, Chemokine - metabolism Cells, Cultured Solubility Hypoxia - immunology Cell Adhesion - drug effects Cell Adhesion - immunology Intercellular Adhesion Molecule-1 - metabolism Animals Signal Transduction - drug effects Coronary Vessels - cytology Endothelium, Vascular - metabolism Signal Transduction - physiology Mice CX3C Chemokine Receptor 1

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