IL-31 Receptor (IL-31RA) Knockout Mice Exhibit Elevated Responsiveness to Oncostatin M
IL-31 Receptor (IL-31RA) Knockout Mice Exhibit Elevated Responsiveness to Oncostatin M
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DOI：
10.4049/jimmunol.0902769
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发表时间：
2010-11-15
影响因子：
4.4
通讯作者：
Dillon, Stacey R.
中科院分区：
文献类型：
--
作者：
Bilsborough, Janine;Mudri, Sherri;Dillon, Stacey R.
IL-31通过异源二聚体受体IL-31 RA和制瘤素M受体（OSMR）发出信号，并且与特应性皮炎（人类中的Th 2细胞因子相关疾病）的发展有关。然而，最近对IL-31 RA敲除（KO）小鼠的研究表明，IL-31信号可能需要负调节Th 2型应答，而不是加剧它们。由于这些研究是在转基因小鼠上进行的，因此我们检查了在两种Th 2细胞相关免疫模型中，用特异性mAb中和IL-31是否会产生与IL-31 RA KO小鼠相似的结果。我们报告在IL-31 RA KO小鼠、用IL-31 mAb处理的小鼠或对照动物之间Ag免疫后淋巴细胞Th 2型细胞因子产生没有差异。第二，我们测试了IL-31 RA KO小鼠中IL-31 RA亚基的缺失是否可以增加OSMR亚基与另一种细胞因子受体gp 130的配对，导致OSM的异二聚体受体的过度表达和对OSM蛋白的反应性增加。我们发现，与野生型同窝对照动物相比，IL-31 RA KO小鼠鼻内OSM激发导致肺中IL-6和血管内皮生长因子的产生增加。此外，PBS激发的IL-31 RA KO小鼠已经具有增加的血管内皮生长因子水平，其通过OSM激发进一步增加。这些数据表明，IL-31 RA缺陷小鼠产生增加的水平的OSM诱导的细胞因子在气道致敏和挑战，这可能是背后的驱动力，以前在这些小鼠中观察到的Th 2型炎症反应的明显恶化。免疫学杂志，2010，185：6023-6030。
IL-31 signals through the heterodimeric receptor IL-31RA and oncostatin M receptor (OSMR), and has been linked with the development of atopic dermatitis, a Th2 cytokine-associated disease in humans. However, recent studies of IL-31RA knockout (KO) mice have suggested that IL-31 signaling may be required to negatively regulate Th2 type responses rather than exacerbate them. Because those studies were performed on genetically modified mice, we examined whether neutralizing IL-31 with a specific mAb would give similar results to IL-31RA KO mice in two Th2 cytokine-associated immune models. We report no difference in lymphocyte Th2-type cytokine production after Ag immunization between IL-31RA KO mice, mice treated with the IL-31 mAb, or control animals. Second, we tested whether the absence of the IL-31RA subunit in IL-31RA KO mice may allow for increased pairing of the OSMR subunit with another cytokine receptor, gp130, resulting in overrepresentation of the heterodimeric receptor for OSM and increased responsiveness to OSM protein. We found that intranasal OSM challenge of IL-31RA KO mice resulted in increased IL-6 and vascular endothelial growth factor production in the lung compared with wild-type littermate control animals. Moreover, PBS-challenged IL-31RA KO mice already had increased levels of vascular endothelial growth factor, which were further increased by OSM challenge. These data imply that IL-31RA-deficient mice produce increased levels of OSM-inducible cytokines during airway sensitization and challenge, which may be the driving force behind the apparent exacerbation of Th2-type inflammatory responses previously observed in these mice. The Journal of Immunology, 2010, 185: 6023-6030.