HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db07-0494v1 57/1/102    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sharp, C. D. Articles by Kevil, C. G. Search for Related Content PubMed PubMed Citation Articles by Sharp, C. D. Articles by Kevil, C. G. Social Bookmarking                What's this?

Stromal Cell–Derived Factor-1/CXCL12 Stimulates Chemorepulsion of NOD/LtJ T-Cell Adhesion to Islet Microvascular Endothelium

¹ Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
² Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, Columbia, South Carolina

Address correspondence and reprint requests to Christopher Kevil, PhD, Department of Pathology, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Hwy., Shreveport, LA 71130-3932. E-mail: ckevil{at}lsuhsc.edu

Key Words: FACS, fluorescence-activated cell sorting • GST, glutathione S-transferase • HBSS, Hanks' balanced salt solution • ICAM-1, intracellular adhesion molecule-1 • NIH, National Institutes of Health • PMSF, phenylmethylsulfonyl fluoride • SDF-1, stromal cell–derived factor-1 • TBS, Tris-buffered saline • TNF-, tumor necrosis factor- • VCAM-1, vascular cell adhesion molecule-1

OBJECTIVE—Diabetogenic T-cell recruitment into pancreatic islets faciltates β-cell destruction during autoimmune diabetes, yet specific mechanisms governing this process are poorly understood. The chemokine stromal cell–derived factor-1 (SDF-1) controls T-cell recruitment, and genetic polymorphisms of SDF-1 are associated with early development of type 1 diabetes.

RESEARCH DESIGN AND METHODS—Here, we examined the role of SDF-1 regulation of diabetogenic T-cell adhesion to islet microvascular endothelium. Islet microvascular endothelial cell monolayers were activated with tumor necrosis factor- (TNF-), subsequently coated with varying concentrations of SDF-1 (1–100 ng/ml), and assayed for T-cell/endothelial cell interactions under physiological flow conditions.

RESULTS—TNF- significantly increased NOD/LtJ T-cell adhesion, which was completely blocked by SDF-1 in a dose-dependent manner, revealing a novel chemorepulsive effect. Conversely, SDF-1 enhanced C57BL/6J T-cell adhesion to TNF-–activated islet endothelium, demonstrating that SDF-1 augments normal T-cell adhesion. SDF-1 chemorepulsion of NOD/LtJ T-cell adhesion was completely reversed by blocking G_i-protein–coupled receptor activity with pertussis toxin. CXCR4 protein expression was significantly decreased in NOD/LtJ T-cells, and inhibition of CXCR4 activity significantly reversed SDF-1 chemorepulsive effects. Interestingly, SDF-1 treatment significantly abolished T-cell resistance to shear-mediated detachment without altering adhesion molecule expression, thus demonstrating decreased integrin affinity and avidity.

CONCLUSIONS—In this study, we have identified a previously unknown novel function of SDF-1 in negatively regulating NOD/LtJ diabetogenic T-cell adhesion, which may be important in regulating diabetogenic T-cell recruitment into islets.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?