CXCR 3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow.
T cells infiltrating the inflamed liver express high levels of CXCR 3 and show enhanced migration to CXCR 3 ligands in chemotactic assays. Moreover, CXCR 3 ligands are up-regulated on hepatic endothelium at sites of T-cell infiltration in chronic hepatitis, and their presence correlates with outcome of inflammatory liver disease. We used a flow-based adhesion assay with human hepatic endothelium to investigate the function of CXCR 3 on lymphocyte adhesion to and transmigration through hepatic endothelium under physiological conditions of blood flow. To more accurately model the function of in vivo activated CXCR 3(high) lymphocytes, we isolated T cells from human liver tissue and studied their behavior in flow-based adhesion assays. We demonstrate that CXCR 3 not only promoted the adhesion of effector T cells to endothelium from flow but also drove transendothelial migration. Moreover, these responses could be stimulated either by endogenous CXCR 3 ligands secreted by the endothelium or by exogenous CXCR 3 ligands derived from other cell types and presented by the endothelium. This study thus demonstrates that activation of CXCR 3 promotes lymphocyte adhesion and transendothelial migration under flow and that human hepatic endothelium can present functionally active chemokines secreted by other cell types within the liver.
Curbishley
Stuart M
SM
Liver Research Group, Institute of Biomedical Research, MRC Centre for Immune Regulation, The University of Birmingham Medical School, Edgbaston, Birmingham, UK B15 2TT. s.m.curbishley@bham.ac.uk
Eksteen
Bertus
B
Gladue
Ron P
RP
Lalor
Patricia
P
Adams
David H
DH
D001659:Biliary Tract / Q000378:metabolism / Q000502:physiology; D001790:Blood Physiological Phenomena; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004727:Endothelium / Q000502:physiology; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008214:Lymphocytes / Q000378:metabolism / Q000502:physiology*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C515187:CXCR3 protein, human; D015815:Cell Adhesion Molecules; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D008024:Ligands; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha