The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1
The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1
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DOI：
10.1073/pnas.0812690106
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发表时间：
2009-06-02
影响因子：
11.1
通讯作者：
Girard, Jean-Philippe
中科院分区：
文献类型：
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作者：
Cayrol, Corinne;Girard, Jean-Philippe
IL-33是IL-1家族的染色质相关细胞因子，其最近与许多疾病相关，包括哮喘、类风湿性关节炎、动脉粥样硬化和心血管疾病。IL-33通过IL-1受体相关蛋白ST 2发出信号，并驱动肥大细胞、2型辅助性T淋巴细胞、嗜碱性粒细胞、嗜酸性粒细胞、不变自然杀伤T细胞和自然杀伤细胞中促炎性和2型辅助性T相关细胞因子的产生。目前认为，IL-33与IL-1 β和IL-18一样，需要通过半胱天冬酶-1加工成成熟形式（IL-33（112-270））以获得生物活性。与目前的观点相反，我们在此报道全长IL-33（1-270）是有活性的，并且caspase-1的加工导致IL- 33失活，而不是活化。我们发现，全长IL-33（1-270）结合并激活ST 2，类似于IL- 33（112-270），caspase-1的切割并不发生在最初提出的位点（Ser（111）），而是发生在IL-1样结构域的第四和第五预测β链之间的残基Asp 178之后。令人惊讶的是，胱天蛋白酶-1切割位点（DGVD（178）G）与胱天蛋白酶-3切割的共有位点相似，并且IL-33也是该凋亡胱天蛋白酶的底物。有趣的是，我们发现在大多数正常人体组织中由内皮细胞组成性表达至高水平的全长IL-33可以在内皮细胞损伤或机械损伤后在细胞外间隙中释放。我们推测，IL-33的功能可能类似于原型alarmins HMGB 1和IL-1 α，作为一种内源性危险信号，在创伤或感染期间警告先天免疫系统的细胞组织损伤。
IL-33 is a chromatin-associated cytokine of the IL-1 family that has recently been linked to many diseases, including asthma, rheumatoid arthritis, atherosclerosis, and cardiovascular diseases. IL-33 signals through the IL-1 receptor-related protein ST2 and drives production of pro-inflammatory and T helper type 2-associated cytokines in mast cells, T helper type 2 lymphocytes, basophils, eosinophils, invariant natural killer T cells, and natural killer cells. It is currently believed that IL-33, like IL-1 beta and IL-18, requires processing by caspase-1 to a mature form (IL-33(112-270)) for biological activity. Contrary to the current belief, we report here that full-length IL-33(1-270) is active and that processing by caspase-1 results in IL- 33 inactivation, rather than activation. We show that full-length IL-33(1-270) binds and activates ST2, similarly to IL- 33(112-270), and that cleavage by caspase-1 does not occur at the site initially proposed (Ser(111)), but rather after residue Asp178 between the fourth and fifth predicted beta-strands of the IL-1-like domain. Surprisingly, the caspase-1 cleavage site (DGVD(178)G) is similar to the consensus site of cleavage by caspase-3, and IL-33 is also a substrate for this apoptotic caspase. Interestingly, we found that full-length IL-33, which is constitutively expressed to high levels by endothelial cells in most normal human tissues, can be released in the extracellular space after endothelial cell damage or mechanical injury. We speculate that IL-33 may function, similarly to the prototypical alarmins HMGB1 and IL-1 alpha, as an endogenous danger signal to alert cells of the innate immune system of tissue damage during trauma or infection.