Yang Jiwei, Rosen Steven D, Bendele Philip, Hemmerich Stefan
Thios Pharmaceuticals Inc,, P,O, Box 20010, Oakland, CA 94620, USA.
BMC Immunol. 2006 Jun 13;7:12. doi: 10.1186/1471-2172-7-12.
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).
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.
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.
白细胞穿越血管的募集对于免疫监视和炎症反应至关重要。淋巴细胞归巢至外周淋巴结是由黏附分子L-选择素介导的，L-选择素可与高内皮微静脉（HEV）上的硫酸化碳水化合物配体结合。这些糖蛋白配体统称为外周淋巴结地址素（PNAd），由功能阻断性单克隆抗体MECA-79定义。这些配体的硫酸化取决于两种HEV表达的N-乙酰葡糖胺6-O-磺基转移酶的作用：GlcNAc6ST-2以及程度稍低的GlcNAc6ST-1。PNAd的诱导也已在包括类风湿关节炎（RA）在内的多种人类炎症性疾病中被证实。
为了确定一种适合研究PNAd在慢性炎症中作用的动物模型，我们检测了小鼠胶原诱导性关节炎中PNAd以及GlcNAc6ST-1和-2的表达。在此我们表明，在用胶原免疫的小鼠中，PNAd表达于关节炎滑膜的脉管系统中，而在对照动物的正常滑膜中不表达。PNAd的这种从头表达与GlcNAc6ST-1和GlcNAc6ST-2转录本的诱导以及GlcNAc6ST-2蛋白的表达密切相关。
我们的结果表明，在小鼠胶原诱导性关节炎中诱导了PNAd以及磺基转移酶GlcNAc6ST-1和2，这表明PNAd拮抗剂或这些酶的抑制剂可能在这种广泛使用的RA小鼠模型中具有治疗益处。
