title: Glucocorticoids Suppress CCR9-Mediated Chemotaxis, Calcium Flux, and Adhesion to MAdCAM-1 in Human T Cells.
abstract: CCR9 expressed on T lymphocytes mediates migration to the small intestine in response to a gradient of CCL25. CCL25-stimulated activation of α4β7 integrin promotes cell adherence to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed by vascular endothelial cells of the intestine, further mediating gut-specific homing. Inflammatory bowel disease is a chronic inflammatory condition that primarily affects the gastrointestinal tract and is characterized by leukocyte infiltration. Glucocorticoids (GCs) are widely used to treat inflammatory bowel disease but their effect on intestinal leukocyte homing is not well understood. We investigated the effect of GCs on the gut-specific chemokine receptor pair, CCR9 and CCL25. Using human peripheral blood-derived T lymphocytes enriched for CCR9 by cell sorting or culturing with all-trans retinoic acid, we measured chemotaxis, intracellular calcium flux, and α4β7-mediated cell adhesion to plate-bound MAdCAM-1. Dexamethasone (DEX), a specific GC receptor agonist, significantly reduced CCR9-mediated chemotaxis and adhesion to MAdCAM-1 without affecting CCR9 surface expression. In contrast, in the same cells, DEX increased CXCR4 surface expression and CXCL12-mediated signaling and downstream functions. The effects of DEX on human primary T cells were reversed by the GC receptor antagonist mifepristone. These results demonstrate that GCs suppress CCR9-mediated chemotaxis, intracellular calcium flux, and α4β7-mediated cell adhesion in vitro, and these effects could contribute to the efficacy of GCs in treating intestinal inflammation in vivo.
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom;
authors.forename: Emily
authors.initials: E
authors.lastname: Wendt
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; and.
authors.forename: Gemma E
authors.initials: GE
authors.lastname: White
authors.affiliation: Experimental Medicine Division, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Ferry
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom;
authors.forename: Michael
authors.initials: M
authors.lastname: Huhn
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; and.
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; satish.keshav@ndm.ox.ac.uk.
authors.forename: Satish
authors.initials: S
authors.lastname: Keshav
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology; D009088:Mucoproteins / Q000378:metabolism*; D054388:Receptors, CCR / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D014212:Tretinoin / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C119309:CC chemokine receptor 9; C108074:CCL25 protein, human; D015815:Cell Adhesion Molecules; D019742:Chemokines, CC; D007136:Immunoglobulins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D054388:Receptors, CCR; D016201:Receptors, Lymphocyte Homing; D014212:Tretinoin; D003907:Dexamethasone