Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity
Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity
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DOI：
10.1073/pnas.1222303110
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发表时间：
2013-05-07
影响因子：
11.1
通讯作者：
Mackall, Crystal L.
中科院分区：
文献类型：
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作者：
Lundstrom, Wangko;Highfill, Steven;Mackall, Crystal L.
与IL-7相比，人可溶性白细胞介素-7受体（sIL-7 R）α以高摩尔过量循环，但其生物学尚不清楚。我们证明sIL-7 R α对IL-7具有中等亲和力，但不结合胸腺基质淋巴细胞生成素。在功能上，sIL 7 R α与细胞相关的IL-7受体竞争以减少IL-7的过度消耗，因此，当细胞因子受到限制时，增强IL-7的生物活性，因为它被认为是在体内。IL-7信号在sIL-7 R α存在下也减少了CD 95和细胞因子信号抑制因子1的表达，这两种调节分子。小鼠模型证实了在存在sIL 7 R α的情况下IL-7的消耗减少，并且还证明了sIL 7 R α对IL-7介导的稳态扩张和实验性自身免疫性脑脊髓炎恶化的增强作用。在多发性硬化和其他几种自身免疫性疾病中，IL 7 R基因型影响易感性。我们在多发性硬化症患者中检测到IL-7基因型易感者sIL-7 R α水平升高，IL-7水平升高，这与体内IL-7消耗减少一致。这项工作表明，sIL-7 R α增强IL-7的生物活性，并提供了一个基础，以解释在个体中观察到的自身免疫性的风险增加与基因型诱导的sIL-7 R α的升高。
Human soluble interleukin-7 receptor (sIL7R)alpha circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7R alpha has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7R alpha competes with cell-associated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited, as it is presumed to be in vivo. IL-7 signaling in the presence of sIL7R alpha also diminishes expression of CD95 and suppressor of cytokine signaling 1, both regulatory molecules. Murine models confirm diminished consumption of IL-7 in the presence of sIL7R alpha and also demonstrate a potentiating effect of sIL7R alpha on IL-7-mediated homeostatic expansion and experimental autoimmune encephalomyelitis exacerbation. In multiple sclerosis and several other autoimmune diseases, IL7R genotype influences susceptibility. We measured increased sIL7R alpha levels, as well as increased IL-7 levels, in multiple sclerosis patients with the predisposing IL7R genotype, consistent with diminished IL-7 consumption in vivo. This work demonstrates that sIL7R alpha potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7R alpha.