RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response
RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response
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DOI：
10.1038/sj.gene.6363861
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发表时间：
2002-05-01
影响因子：
5
通讯作者：
Schmidt, AM
中科院分区：
文献类型：
--
作者：
Hofmann, MA;Drury, S;Schmidt, AM
晚期糖基化终产物受体（RAGE）及其促炎S100/calgranulin配体在类风湿关节炎（RA）患者的关节中富集，并增强免疫/炎症反应。在炎症性关节炎模型中，用牛II型胶原免疫和攻击小鼠的RAGE阻断抑制了关节炎的临床和组织学证据，同时降低了受影响组织中tnf - α、IL-6和基质金属蛋白酶（MMP） 3、9和13的水平。RAGE关键区域内的等位基因变异可能影响这些促炎机制，从而使个体易发生炎症反应。RAGE基因在受体的配体结合区域内存在多态性，包括82位的甘氨酸到丝氨酸的变化。与表达RAGE 82G等位基因的细胞相比，携带RAGE 82S等位基因的细胞在被原型S100/calgranulin连接后表现出更强的结合和细胞因子/MMP的产生。在人类受试者中，一项病例对照研究表明，与对照组相比，82S等位基因在RA患者中的患病率增加。这些数据表明，RAGE 82S在S100/calgranulins参与时上调炎症反应，因此可能有助于增强免疫/炎症性疾病的促炎机制。
The receptor for advanced glycation end products (RAGE) and its proinflammatory S100/calgranulin ligands are enriched in joints of subjects with rheumatoid arthritis (RA) and amplify the immune/inflammatory response. In a model of inflammatory arthritis, blockade of RAGE in mice immunized and challenged with bovine type II collagen suppressed clinical and histologic evidence of arthritis, in parallel with diminished levels of TNF-alpha, IL-6, and matrix metalloproteinases (MMP) 3, 9 and 13 in affected tissues. Allelic variation within key domains of RAGE may influence these proinflammatory mechanisms, thereby predisposing individuals to heightened inflammatory responses. A polymorphism of the RAGE gene within the ligand-binding domain of the receptor has been identified, consisting of a glycine to serine change at position 82. Cells bearing the RAGE 82S allele displayed enhanced binding and cytokine/MMP generation following ligation by a prototypic S100/calgranulin compared with cells expressing the RAGE 82G allele. In human subjects, a case-control study demonstrated an increased prevalence of the 82S allele in patients with RA compared with control subjects. These data suggest that RAGE 82S upregulates the inflammatory response upon engagement of S100/calgranulins, and, thereby, may contribute to enhanced proinflammatory mechanisms in immune/inflammatory diseases.