Cancer and Inflammation Program, Center for Cancer Research, Frederick, MD, USA.
Blood. 2011 Jan 13;117(2):575-84. doi: 10.1182/blood-2010-05-285908. Epub 2010 Oct 22.
The interleukin (IL)-22R1 chain of the heterodimeric IL-22 receptor is not expressed on normal leukocytes, but this receptor is expressed on T cells from anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large cell lymphoma (ALCL) patients. To investigate the consequences of aberrant expression of this receptor on lymphocytes, we generated transgenic mice that express IL-22R1 on lymphocytes. The health of these animals progressively deteriorated at 8 to 12 weeks of age, as they displayed respiratory distress, rough coat and sluggish movement, and subsequent lethality due to multiorgan inflammation. The IL-22R1 transgenic animals developed neutrophilia that correlated with increased levels of circulating IL-17 and granulocyte colony-stimulating factor. In addition, these mice had increased serum IL-22 levels, suggesting that T cells expressing IL-22R1 generate IL-22 in a positive autoregulatory loop. As a result of the mouse model findings, we analyzed circulating cytokine levels in ALK(+)ALCL patients and detected elevated levels of IL-22, IL-17, and IL-8 in untreated patient samples. Importantly, IL-22 and IL-17 were undetectable in all patients who were in complete remission after chemotherapy. This study documents a previously unknown role of IL-22R1 in inflammation and identifies the involvement of IL-22R1/IL-22 in ALK(+)ALCL.
白细胞介素 (IL)-22R1 链是二聚体 IL-22 受体的一部分，在正常白细胞中不表达，但在间变性淋巴瘤激酶阳性 (ALK(+))间变性大细胞淋巴瘤 (ALCL) 患者的 T 细胞中表达。为了研究这种受体在淋巴细胞上异常表达的后果，我们生成了在淋巴细胞上表达 IL-22R1 的转基因小鼠。这些动物的健康状况在 8 至 12 周龄时逐渐恶化，表现为呼吸困难、毛发粗糙和行动迟缓，随后由于多器官炎症而死亡。IL-22R1 转基因动物出现中性粒细胞增多，与循环中 IL-17 和粒细胞集落刺激因子水平升高相关。此外，这些小鼠的血清 IL-22 水平升高，表明表达 IL-22R1 的 T 细胞在正反馈环中产生 IL-22。基于小鼠模型的研究结果，我们分析了 ALK(+)ALCL 患者的循环细胞因子水平，并在未经治疗的患者样本中检测到 IL-22、IL-17 和 IL-8 的水平升高。重要的是，在所有化疗后完全缓解的患者中，均未检测到 IL-22 和 IL-17。本研究证明了 IL-22R1 在炎症中的一个未知作用，并确定了 IL-22R1/IL-22 在 ALK(+)ALCL 中的参与。
