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.

Chemokines and Chemokine Receptors as Therapeutic Targets in Inflammatory Bowel Disease; Pitfalls and Promise

“…The biological role of the CCR9-CCL25 axis and the evidence implicating CCR9, and CCL25 in gut inflammation in both human and murine IBD, suggest this is an appropriate pathway to target therapeutically. 10 , 29 , 39 , 50 , 51 However, the involvement of CCR9 and CCL25 in immune regulation and tolerance raises valid concerns that under some circumstances inhibition could be detrimental. Studies of immunoblockade of CCR9 and CCL25 in the Samp1/Yit model, showing an effect on early but not late inflammation, suggest that timing of intervention may also be important, with the possibility of a role in preventing or inducing rather than maintaining remission.…”

Dexamethasone Down-regulates Osteocalcin in Bone Cells through Leptin Pathway

“…Glucocorticoids have direct effects on osteoblast, osteocyte, and osteoclast function resulting in reduced bone remodeling and diminished repair of microdamage to bone. In addition to the direct effects on bone cells, glucocorticoids also have effects on the intestine, kidneys, gonads, and probably parathyroid glands, which may contribute to osteoporosis 6 .…”

Detection and characterization of murine colitis and carcinogenesis by molecularly targeted contrast-enhanced ultrasound

“…Therapeutical blockade of T-cell homing via the integrin α4β7 and the cellular adhesion molecule MAdCAM-1 has been intensively studied during the last years as T cells represent a key player in the perpetuation of intestinal inflammation[67]. Most recent work by Wendt et al[68] demonstrated that even classic glucocorticoids act partially via MAdCAM-1 by reducing C-C chemokine receptor type 9-mediated chemotaxis of T-lymphocytes. Agents targeting leukocyte trafficking have been developed and some anti-integrin antibodies are already available for IBD therapy while others will follow in the near future[69].…”