A HEV-restricted sulfotransferase is expressed in rheumatoid arthritis synovium and is induced by lymphotoxin-alpha/beta and TNF-alpha in cultured endothelial cells

BMC Immunol. 2005 Mar 7;6:6. doi: 10.1186/1471-2172-6-6.

Abstract

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.

Conclusion: 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigens, Surface / biosynthesis
  • Antigens, Surface / genetics
  • Arthritis, Rheumatoid / enzymology*
  • Arthritis, Rheumatoid / pathology
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Chemotaxis, Leukocyte / physiology*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / cytology*
  • Humans
  • L-Selectin / physiology
  • Lymphotoxin-alpha / pharmacology*
  • Lymphotoxin-beta
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / pharmacology*
  • Receptors, Lymphocyte Homing / physiology
  • Sulfotransferases / biosynthesis*
  • Sulfotransferases / genetics
  • Synovial Membrane / metabolism*
  • Synovial Membrane / pathology
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Venules / cytology

Substances

  • Antigens, Surface
  • L-selectin counter-receptors
  • LTB protein, human
  • Lymphotoxin-alpha
  • Lymphotoxin-beta
  • Membrane Proteins
  • Receptors, Lymphocyte Homing
  • Tumor Necrosis Factor-alpha
  • L-Selectin
  • Sulfotransferases
  • carbohydrate sulfotransferases