Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France.
J Immunol. 2012 Apr 1;188(7):3488-95. doi: 10.4049/jimmunol.1101977. Epub 2012 Feb 27.
IL-33 (previously known as NF from high endothelial venules) is an IL-1 family cytokine that signals through the ST2 receptor and drives cytokine production in mast cells, basophils, eosinophils, invariant NKT and NK cells, Th2 lymphocytes, and type 2 innate immune cells (natural helper cells, nuocytes, and innate helper 2 cells). Little is known about endogenous IL-33; for instance, the cellular sources of IL-33 in mouse tissues have not yet been defined. In this study, we generated an Il-33-LacZ gene trap reporter strain (Il-33(Gt/Gt)) and used this novel tool to analyze expression of endogenous IL-33 in vivo. We found that the Il-33 promoter exhibits constitutive activity in mouse lymphoid organs, epithelial barrier tissues, brain, and embryos. Immunostaining with anti-IL-33 Abs, using Il-33(Gt/Gt) (Il-33-deficient) mice as control, revealed that endogenous IL-33 protein is highly expressed in mouse epithelial barrier tissues, including stratified squamous epithelia from vagina and skin, as well as cuboidal epithelium from lung, stomach, and salivary gland. Constitutive expression of IL-33 was not detected in blood vessels, revealing the existence of species-specific differences between humans and mice. Importantly, IL-33 protein was always localized in the nucleus of producing cells with no evidence for cytoplasmic localization. Finally, strong expression of the Il-33-LacZ reporter was also observed in inflamed tissues, in the liver during LPS-induced endotoxin shock, and in the lung alveoli during papain-induced allergic airway inflammation. Together, our findings support the possibility that IL-33 may function as a nuclear alarmin to alert the innate immune system after injury or infection in epithelial barrier tissues.
IL-33（以前称为高内皮静脉中的 NF）是一种白细胞介素 1 家族细胞因子，通过 ST2 受体信号传导，驱动肥大细胞、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、Th2 淋巴细胞和 2 型先天免疫细胞（天然辅助细胞、nuocytes 和先天辅助 2 细胞）产生细胞因子。关于内源性 IL-33 的了解甚少；例如，尚未确定小鼠组织中 IL-33 的细胞来源。在这项研究中，我们生成了一个 Il-33-LacZ 基因陷阱报告基因系（Il-33(Gt/Gt)），并使用该新型工具分析内源性 IL-33 在体内的表达。我们发现，Il-33 启动子在小鼠淋巴器官、上皮屏障组织、大脑和胚胎中具有组成型活性。使用抗-IL-33 Abs 进行免疫染色，使用 Il-33(Gt/Gt)（Il-33 缺陷）小鼠作为对照，结果表明内源性 IL-33 蛋白在小鼠上皮屏障组织中高度表达，包括阴道和皮肤的复层鳞状上皮以及肺、胃和唾液腺的立方上皮。在血管中未检测到 IL-33 的组成型表达，这表明人类和小鼠之间存在种属特异性差异。重要的是，IL-33 蛋白始终定位于产生细胞的核内，没有细胞质定位的证据。最后，在炎症组织中也观察到 Il-33-LacZ 报告基因的强烈表达，在 LPS 诱导的内毒素休克期间肝脏中以及在木瓜蛋白酶诱导的过敏性气道炎症期间肺肺泡中。总之，我们的研究结果支持 IL-33 可能作为核警报素在上皮屏障组织受伤或感染后向先天免疫系统发出警报的可能性。
