Serglycin inhibits the classical and lectin pathways of complement via its glycosaminoglycan chains: Implications for multiple myeloma
Serglycin inhibits the classical and lectin pathways of complement via its glycosaminoglycan chains: Implications for multiple myeloma
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DOI：
10.1002/eji.201040429
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发表时间：
2011-02-01
影响因子：
5.4
通讯作者：
Theocharis, Achilleas D.
中科院分区：
文献类型：
--
作者：
Skliris, Antonis;Happonen, Kaisa E.;Theocharis, Achilleas D.
Serglycin （SG）是一种由造血细胞表达的蛋白多糖，由多发性骨髓瘤（MM）细胞组成性分泌。SG参与各种炎症事件的调节。我们发现，人MM细胞系分泌的SG抑制补体的经典途径和凝集素途径，而不影响替代途径的活性。SG的抑制作用是由于与C1q和甘露糖结合凝集素（MBL）的直接相互作用。c1q结合是通过SG的糖胺聚糖部分介导的，而MBL则是另外结合到SG蛋白核心。在硫酸e型软骨素的存在下，SG与C1q以及MBL之间的相互作用减弱。此外，我们将SG结合位点定位在C1q的胶原样茎上。SG和C1q以及MBL之间的相互作用是离子性质的，只有与MBL的相互作用部分依赖于钙的存在。我们发现，与健康对照相比，MM患者血清SG水平升高。此外，我们发现骨髓瘤浆细胞中表达的SG可以保护这些细胞免受抗胸腺细胞免疫球蛋白诱导的补体活化。这可能在免疫治疗期间保护骨髓瘤细胞并促进恶性细胞的存活。
Serglycin (SG) is a proteoglycan expressed by hematopoietic cells and is constitutively secreted by multiple myeloma (MM) cells. SG participates in the regulation of various inflammatory events. We found that SG secreted by human MM cell lines inhibits both the classical and lectin pathways of complement, without influencing alternative pathway activity. The inhibitory effect of SG is due to direct interactions with C1q and mannose-binding lectin (MBL). C1q-binding is mediated through the glycosaminoglycan moieties of SG, whereas MBL binds additionally to SG protein core. Interactions between SG and C1q as well as MBL are diminished in the presence of chondroitin sulfate type E. In addition, we localized the SG-binding site to the collagen-like stalk of C1q. Interactions between SG and C1q as well as MBL are ionic in character and only the interaction with MBL was found to be partially dependent on the presence of calcium. We found the serum levels of SG to be elevated in patients with MM compared to healthy controls. Moreover, we found that SG expressed from myeloma plasma cells protects these cells from complement activation induced by treatment with anti-thymocyte immunoglobulins. This might protect myeloma cells during immunotherapy and promote survival of malignant cells.