Induction of PNAd and N-acetylglucosamine 6-O-sulfotransferases 1 and 2 in mouse collagen-induced arthritis.
BACKGROUND
Leukocyte recruitment across blood vessels is fundamental to immune surveillance and inflammation. Lymphocyte homing to peripheral lymph nodes is mediated by the adhesion molecule, L-selectin, which binds to sulfated carbohydrate ligands on high endothelial venules (HEV). These glycoprotein ligands are collectively known as peripheral node addressin (PNAd), as defined by the function-blocking monoclonal antibody known as MECA-79. The sulfation of these ligands depends on the action of two HEV-expressed N-acetylglucosamine 6-O-sulfotransferases: GlcNAc6ST-2 and to a lesser degree GlcNAc6ST-1. Induction of PNAd has also been shown to occur in a number of human inflammatory diseases including rheumatoid arthritis (RA).


RESULTS
In order to identify an animal model suitable for investigating the role of PNAd in chronic inflammation, we examined the expression of PNAd as well as GlcNAc6ST-1 and -2 in collagen-induced arthritis in mice. Here we show that PNAd is expressed in the vasculature of arthritic synovium in mice immunized with collagen but not in the normal synovium of control animals. This de novo expression of PNAd correlates strongly with induction of transcripts for both GlcNAc6ST-1 and GlcNAc6ST-2, as well as the expression of GlcNAc6ST-2 protein.


CONCLUSIONS
Our results demonstrate that PNAd and the sulfotransferases GlcNAc6ST-1 and 2 are induced in mouse collagen-induced arthritis and suggest that PNAd antagonists or inhibitors of the enzymes may have therapeutic benefit in this widely-used mouse model of RA.
Yang
Jiwei
J
Thios Pharmaceuticals Inc,, P,O, Box 20010, Oakland, CA 94620, USA. jyang@geron.com
Rosen
Steven D
SD
Bendele
Philip
P
Hemmerich
Stefan
S
D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis* / Q000235:genetics; D001169:Arthritis, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics; D013583:Synovial Membrane / Q000098:blood supply / Q000378:metabolism; D015854:Up-Regulation; D000097811:Carbohydrate Sulfotransferases
D000954:Antigens, Surface; D008565:Membrane Proteins; D012333:RNA, Messenger; D015238:Sulfotransferases; D000097811:Carbohydrate Sulfotransferases; C069886:L-selectin counter-receptors