Interleukin-33 (IL-33) is the latest member of the IL-1 family that has become very attractive since the discovery of its major target cells, the innate lymphoid cells type 2 (ILC2), involved in the initiation of the type 2 immune response (secretion of IL-5 and IL-13) during parasitic infection and allergic diseases such as asthma. IL-33 is a chromatin-associated protein as it possesses in its N-terminus, a chromatin-binding domain, and is constitutively expressed in the nuclei of endothelial cells and in epithelial cells of tissues exposed to the environment. It is however, essential for IL-33 to be extracellularly released to bind to its receptor ST2 through the C-terminus portion of the protein in order to induce the inflammatory and type 2 responses. Like other IL-1 family members, IL-33 does not possess any signal peptide and may be released through unconventional secretory mechanisms or following cell damage and necrosis. It was initially believed that IL-33, like IL-1β and IL-18, requires processing by caspase-1 to be released, and for biological activity. On the contrary, full length IL-33 is biologically active, and processing by caspases results rather in IL-33 inactivation. Moreover, it has been recently shown that the bioactivity of IL-33 can be increased by inflammatory proteases secreted in the microenvironment, similarly to IL-1α, IL-1β and IL-18. This review will summarize recent progress on how IL-33 is released and processed compared with the other IL-1 family members, and how the immune cells recruited to the site of injury can regulate the disease-associated function of IL-33.

中文翻译：

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IL-33加工和分泌的机制：IL-1家族成员之间的异同。

白介素33（IL-33）是IL-1家族的最新成员，自发现其主要靶细胞2型先天淋巴样细胞（ILC2）以来，它就变得非常有吸引力，该细胞参与了2型的启动寄生虫感染和过敏性疾病（例如哮喘）中的免疫应答（IL-5和IL-13的分泌）。IL-33是一种与染色质相关的蛋白，因为它在其N端具有染色质结合域，并在内皮细胞核和暴露于环境的组织的上皮细胞中组成性表达。然而，IL-33必需通过蛋白质的C端部分在细胞外释放以与其受体ST2结合，以诱导炎症反应和2型反应。与其他IL-1家庭成员一样，IL-33不具有任何信号肽，可能通过非常规的分泌机制或在细胞损伤和坏死后释放。最初认为，IL-33与IL-1β和IL-18一样，需要被caspase-1释放并具有生物学活性。相反，全长IL-33具有生物学活性，而胱天蛋白酶处理可导致IL-33失活。而且，最近已经显示出，与IL-1α，IL-1β和IL-18相似，微环境中分泌的炎性蛋白酶可以提高IL-33的生物活性。这篇综述将总结与其他IL-1家族成员相比如何释放和加工IL-33的最新进展，以及募集到损伤部位的免疫细胞如何调节IL-33与疾病相关的功能。