Document Detail


Tumor necrosis factor-alpha in diabetic plasma increases the activity of core 2 GlcNAc-T and adherence of human leukocytes to retinal endothelial cells: significance of core 2 GlcNAc-T in diabetic retinopathy.
MedLine Citation:
PMID:  15504978     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A large body of evidence now implicates increased leukocyte-endothelial cell adhesion as a key early event in the development of diabetic retinopathy. We recently reported that raised activity of the glycosylating enzyme core 2 beta 1,6-N-acetylglucosaminyltransferase (GlcNAc-T) through protein kinase C (PKC)beta2-dependent phosphorylation plays a fundamental role in increased leukocyte-endothelial cell adhesion and capillary occlusion in retinopathy. In the present study, we demonstrate that following exposure to plasma from diabetic patients, the human promonocytic cell line U937 exhibits a significant elevation in core 2 GlcNAc-T activity and increased adherence to cultured retinal capillary endothelial cells. These effects of diabetic plasma on enzyme activity and cell adhesion, mediated by PKCbeta2-dependent phosphorylation of the core 2 GlcNAc-T protein, were found to be triggered by increased plasma levels of tumor necrosis factor (TNF)-alpha. Levels of enzyme activity in plasma-treated U937 cells were closely dependent on the severity of diabetic retinopathy, with the highest values observed upon treatment with plasma of patients affected by proliferative retinopathy. Furthermore, we noted much higher correlation, as compared with control subjects, between increased values of core 2 GlcNAc-T activity and cell adhesion properties. Based on the prominent role of TNF-alpha in the development of diabetic retinopathy, these observations further validate the significance of core 2 GlcNAc-T in the pathogenesis of capillary occlusion, thereby enhancing the therapeutic potential of specific enzyme inhibitors.
Authors:
Bahaedin M Ben-Mahmud; Giovanni E Mann; Alessandro Datti; Aldo Orlacchio; Eva M Kohner; Rakesh Chibber
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Diabetes     Volume:  53     ISSN:  0012-1797     ISO Abbreviation:  Diabetes     Publication Date:  2004 Nov 
Date Detail:
Created Date:  2004-10-26     Completed Date:  2005-01-12     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2968-76     Citation Subset:  AIM; IM    
Affiliation:
Centre for Cardiovascular BiologyMedicine, 2nd floor, New Hunt's House, Guy's, King's & St. Thomas' School of Biomedical Sciences, King's College London, London, SE1 1UL, UK.
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MeSH Terms
Descriptor/Qualifier:
Adult
Capillaries / physiology
Cell Adhesion / physiology*
Cells, Cultured
Diabetes Mellitus, Type 1 / physiopathology*
Diabetes Mellitus, Type 2 / physiopathology*
Diabetic Retinopathy / blood,  enzymology,  physiopathology*
Endothelium, Vascular / cytology,  physiology,  physiopathology*
Female
Humans
Leukocytes / physiology*
Male
Middle Aged
N-Acetylglucosaminyltransferases / metabolism*
Protein Kinase C / metabolism
Recombinant Proteins / pharmacology
Retinal Vessels / physiopathology*
Tumor Necrosis Factor-alpha / pharmacology,  physiology*
Chemical
Reg. No./Substance:
0/Recombinant Proteins; 0/Tumor Necrosis Factor-alpha; EC 2.4.1.-/N-Acetylglucosaminyltransferases; EC 2.4.1.143/alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase; EC 2.7.11.13/Protein Kinase C

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