title: CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow.
abstract: Inflammatory bowel disease is characterized by the recruitment of lymphocytes to the gut via mucosal vessels. Chemokines are believed to trigger alpha(4)beta(1)- and alpha(4)beta(7)-integrin-mediated adhesion to vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on mucosal vessels, although the contribution of each pathway and the chemokines involved are not well characterized. These interactions occur under conditions of hemodynamic shear, which is critical in determining how lymphocytes integrate chemokine signals to promote transmigration. To define the role of specific chemokines in mediating lymphocyte adhesion to VCAM-1 and MAdCAM-1, we studied the ability of immobilized chemokines to activate adhesion of human lymphocytes in a flow-based adhesion assay. Adhesion to immobilized MAdCAM-1 was alpha(4)beta(7) dependent, with no contribution from alpha(4)beta(1), whereas alpha(4)beta(1) mediated rolling and static adhesion on VCAM-1. Immobilized CC-chemokine ligand (CCL) 25 and CCL28 were both able to trigger alpha(4)beta(7)-dependent lymphocyte arrest on MAdCAM-1 under shear, highlighting a potential role for these chemokines in the arrest of lymphocytes on postcapillary venules in the gut. Neither had any effect on adhesion to VCAM-1, suggesting that they selectively trigger alpha(4)beta(7)-mediated adhesion. Immobilized CCL21, CCL25, CCL28, and CXC-chemokine ligand (CXCL) 12 all converted rolling adhesion to static arrest on MAdCAM-1 by activating lymphocyte integrins, but only CCL21 and CXCL12 also triggered a motile phenotype characterized by lamelipodia and uropod formation. Thus alpha(4)beta(1)/VCAM-1 and alpha(4)beta(7)/MAdCAM-1 operate independently to support lymphocyte adhesion from flow, and chemokines may act in concert with one chemokine triggering integrin-mediated arrest and a second chemokine promoting motility and transendothelial migration.
authors.affiliation: Liver Research Group, Medical Research Council Centre for Immune Regulation, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Miles
authors.forename: Evaggelia
authors.initials: E
authors.lastname: Liaskou
authors.forename: Bertus
authors.initials: B
authors.lastname: Eksteen
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Lalor
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules; D054421:Chemokine CCL21 / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000494:pharmacology; D019742:Chemokines, CC / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000473:pathology; D039441:Integrin alpha4 / Q000032:analysis; D039041:Integrin alpha4beta1 / Q000276:immunology / Q000378:metabolism; D016023:Integrins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D036904:Leukocyte Rolling / Q000187:drug effects / Q000502:physiology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009088:Mucoproteins / Q000235:genetics / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000032:analysis; D012212:Rheology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000737:chemistry; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000906:Antibodies; C515478:CCL21 protein, human; C108074:CCL25 protein, human; C414047:CCL28 protein, human; C515255:CXCL12 protein, human; D015815:Cell Adhesion Molecules; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D007136:Immunoglobulins; D039041:Integrin alpha4beta1; D016023:Integrins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D019707:Receptors, Chemokine; D019010:Vascular Cell Adhesion Molecule-1; C071777:integrin alpha4beta7; D039441:Integrin alpha4; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins