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Stromal cell-derived factor-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T-cell adhesion to islet microvascular endothelium.
Diabetes. 2008 Jan; 57(1):102-12.D

Abstract

OBJECTIVE

Diabetogenic T-cell recruitment into pancreatic islets facilitates beta-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-alpha (TNF-alpha), 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-alpha 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-alpha-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)alpha-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.

Authors+Show Affiliations

Department of Pathology, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Hwy., Shreveport, LA 71130-3932, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17909096

Citation

Sharp, Christopher D., et al. "Stromal Cell-derived factor-1/CXCL12 Stimulates Chemorepulsion of NOD/LtJ T-cell Adhesion to Islet Microvascular Endothelium." Diabetes, vol. 57, no. 1, 2008, pp. 102-12.
Sharp CD, Huang M, Glawe J, et al. Stromal cell-derived factor-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T-cell adhesion to islet microvascular endothelium. Diabetes. 2008;57(1):102-12.
Sharp, C. D., Huang, M., Glawe, J., Patrick, D. R., Pardue, S., Barlow, S. C., & Kevil, C. G. (2008). Stromal cell-derived factor-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T-cell adhesion to islet microvascular endothelium. Diabetes, 57(1), 102-12.
Sharp CD, et al. Stromal Cell-derived factor-1/CXCL12 Stimulates Chemorepulsion of NOD/LtJ T-cell Adhesion to Islet Microvascular Endothelium. Diabetes. 2008;57(1):102-12. PubMed PMID: 17909096.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stromal cell-derived factor-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T-cell adhesion to islet microvascular endothelium. AU - Sharp,Christopher D, AU - Huang,Meng, AU - Glawe,John, AU - Patrick,D Ross, AU - Pardue,Sible, AU - Barlow,Shayne C, AU - Kevil,Christopher G, Y1 - 2007/10/01/ PY - 2007/10/3/pubmed PY - 2008/1/16/medline PY - 2007/10/3/entrez SP - 102 EP - 12 JF - Diabetes JO - Diabetes VL - 57 IS - 1 N2 - OBJECTIVE: Diabetogenic T-cell recruitment into pancreatic islets facilitates beta-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-alpha (TNF-alpha), 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-alpha 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-alpha-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)alpha-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. SN - 1939-327X UR - https://www.unboundmedicine.com/medline/citation/17909096/Stromal_cell_derived_factor_1/CXCL12_stimulates_chemorepulsion_of_NOD/LtJ_T_cell_adhesion_to_islet_microvascular_endothelium_ L2 - https://diabetes.diabetesjournals.org/lookup/pmidlookup?view=long&pmid=17909096 DB - PRIME DP - Unbound Medicine ER -