Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding
Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding
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DOI：
10.4049/jimmunol.171.12.6814
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发表时间：
2003-12-15
影响因子：
4.4
通讯作者：
Levine, SJ
中科院分区：
文献类型：
--
作者：
Cui, XL;Rouhani, FN;Levine, SJ
II型IL-1诱骗受体（IL-1RII）的细胞外结构域的蛋白水解裂解产生可溶性IL-1结合蛋白，通过结合游离IL-1来防止过度的生物活性。在这项研究中，我们报道了一种氨肽酶，TNFR1脱落的氨肽酶调节剂（ARTS-1），是IL-1RII脱落所必需的。共免疫沉淀实验证明内源性膜相关的ARTS-1与47-kDa的IL-IRII之间存在关联，这与膜结合受体的外畴切割一致。ARTS-1蛋白表达与IL-1RII脱落之间存在直接相关性，因为过表达ARTS-1的细胞系增加了IL-1RII脱落，降低了膜相关的IL-1RII。基础IL-1RII脱落在ARTS-1敲除细胞系中不存在，这表明art -1是构成性IL-1RII脱落所必需的。同样，pma介导的1L-1RII脱落几乎完全依赖于arts -1。ARTS-1的表达也增强了离子霉素诱导的IL-1RII的脱落。ARTS-1没有改变细胞膜相关IL-1RI或IL-1R拮抗剂从ARTS-1细胞系中释放的水平，这表明ARTS-1促进IL-1R家族成员脱落的能力可能是针对IL-1RII特异性的。此外，过度表达ARTS-1的细胞增加IL-1RII脱落会减弱il -1 β的生物活性。我们得出结论，ARTS-1增强IL-1RII脱落的能力代表了一种新的机制，通过这种机制可以调节il -1诱导的细胞事件。由于ARTS-1还促进结构无关的55-kDa、I型TNF受体和IL-6R的脱落，我们提出ARTS-1可能通过增加细胞因子受体的脱落在调节先天免疫和炎症反应中发挥重要作用。
Proteolytic cleavage of the extracellular domain of the type II IL-1 decoy receptor (IL-1RII) generates soluble IL-1-binding proteins that prevent excessive bioactivity by binding free IL-1. In this study we report that an aminopeptidase, aminopeptidase regulator of TNFR1 shedding (ARTS-1), is required for IL-1RII shedding. Coimmunoprecipitation experiments demonstrate an association between endogenous membrane-associated ARTS-1 and a 47-kDa IL-IRII, consistent with ectodomain cleavage of the membrane-bound receptor. A direct correlation exists between ARTS-1 protein expression and IL-1RII shedding, as cell lines overexpressing ARTS-1 have increased IL-1RII shedding and decreased membrane-associated IL-1RII. Basal IL-1RII shedding is absent from ARTS-1 knockout cell lines, demonstrating that ARTS-1 is required for constitutive 1L-1RII shedding. Similarly, PMA-mediated 1L-1RII shedding is almost entirely ARTS-1-dependent. ARTS-1 expression also enhances ionomycin-induced IL-1RII shedding. ARTS-1 did not alter levels of membrane-associated IL-1RI or IL-1R antagonist release from ARTS-1 cell lines, which suggests that the ability of ARTS-1 to promote shedding of IL-1R family members may be specific for IL-1RII Further, increased IL-1RII shedding by ARTS-1-overexpressing cells attenuates the biological activity of IL-1beta. We conclude that the ability of ARTS-1 to enhance IL-1RII shedding represents a new mechanism by which IL-1-induced cellular events can be modulated. As ARTS-1 also promotes the shedding of the structurally unrelated 55-kDa, type I TNF receptor and the IL-6R, we propose that ARTS-1 may play an important role in regulating innate immune and inflammatory responses by increasing cytokine receptor shedding.