A HEV-restricted sulfotransferase is expressed in rheumatoid arthritis synovium and is induced by lymphotoxin-alpha/beta and TNF-alpha in cultured endothelial cells.
BACKGROUND
The recruitment of lymphocytes to secondary lymphoid organs relies on interactions of circulating cells with high endothelial venules (HEV). HEV are exclusive to these organs under physiological conditions, but they can develop in chronically-inflamed tissues. The interaction of L-selectin on lymphocytes with sulfated glycoprotein ligands on HEV results in lymphocyte rolling, which represents the initial step in lymphocyte homing. HEV expression of GlcNAc6ST-2 (also known as HEC-GlcNAc6ST, GST-3, LSST or CHST4), an HEV-restricted sulfotransferase, is essential for the elaboration of L-selectin functional ligands as well as a critical epitope recognized by MECA-79 mAb.


RESULTS
We examined the expression of GlcNAc6ST-2 in relationship to the MECA-79 epitope in rheumatoid arthritis (RA) synovial vessels. Expression of GlcNAc6ST-2 was specific to RA synovial tissues as compared to osteoarthritis synovial tissues and localized to endothelial cells of HEV-like vessels and small flat-walled vessels. Double MECA-79 and GlcNAc6ST-2 staining showed colocalization of the MECA-79 epitope and GlcNAc6ST-2. We further found that both TNF-alpha and lymphotoxin-alphabeta induced GlcNAc6ST-2 mRNA and protein in cultured human umbilical vein endothelial cells.


CONCLUSIONS
These observations demonstrate that GlcNAc6ST-2 is induced in RA vessels and provide potential cytokine pathways for its induction. GlcNAc6ST-2 is a novel marker of activated vessels within RA ectopic lymphoid aggregates. This enzyme represents a potential therapeutic target for RA.
Pablos
José L
JL
Servicio de Reumatología y Unidad de Investigación, Hospital 12 de Octubre, 28041 Madrid, Spain. jlpablos@h12o.es
Santiago
Begoña
B
Tsay
Durwin
D
Singer
Mark S
MS
Palao
Guillermo
G
Galindo
María
M
Rosen
Steven D
SD
D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D019041:L-Selectin / Q000502:physiology; D008233:Lymphotoxin-alpha / Q000494:pharmacology*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014699:Venules / Q000166:cytology; D000097811:Carbohydrate Sulfotransferases
D000954:Antigens, Surface; D019041:L-Selectin; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D016201:Receptors, Lymphocyte Homing; D015238:Sulfotransferases; D014409:Tumor Necrosis Factor-alpha; D000097811:Carbohydrate Sulfotransferases; C069886:L-selectin counter-receptors; C505886:LTB protein, human