Nagakura Chihiro, Negishi Yusuke, Tsukimoto Mitsutoshi, Itou Satomi, Kondo Takeshi, Takeda Ken, Kojima Shuji
Department of Radiation Biosciences, Tokyo University of Science (TUS), 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan.
Research Institute for Science and Technology, Tokyo University of Science (TUS), 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan.
Toxicology. 2014 Aug 1;322:61-8. doi: 10.1016/j.tox.2014.03.010. Epub 2014 May 2.
We have previously reported that P2Y11 receptor mediates IFN-γ-induced IL-6 production in human keratinocytes, suggesting the importance of purinergic signaling in skin inflammatory diseases. In this study, the involvement of various P2 receptors in IL-6 production induced by silica nanoparticle 30 (SNP30) was examined in a human keratinocyte cell line, HaCaT. Exposure to SNP30 increased IL-6 production in the cells. Ecto-nucleotidase (apyrase), a non-selective antagonist of P2Y receptors (suramin), and a selective P2Y11 receptor antagonist (NF157) all inhibited IL-6 production. Nucleotides such as ATP and UTP themselves also significantly increased IL-6 production in the cells. It was further confirmed that ATP was released from HaCaT cells exposed to SNP30. These results support the possible role of ATP in SNP30-induced IL-6 production by HaCaT cells. In conclusion, these data demonstrate that P2Y11 receptor also mediates SNP30-induced IL-6 production in human keratinocytes, confirming that the ATP-P2Y11 purinergic signaling is a common pathway of IL-6 production leading to induction of skin inflammatory diseases.
我们之前曾报道，P2Y11受体介导人角质形成细胞中干扰素-γ诱导的白细胞介素-6生成，提示嘌呤能信号在皮肤炎症性疾病中的重要性。在本研究中，我们检测了人角质形成细胞系HaCaT中各种P2受体在二氧化硅纳米颗粒30（SNP30）诱导的白细胞介素-6生成中的作用。暴露于SNP30可增加细胞中白细胞介素-6的生成。胞外核苷酸酶（腺苷三磷酸双磷酸酶）、P2Y受体的非选择性拮抗剂（苏拉明）以及选择性P2Y11受体拮抗剂（NF157）均抑制白细胞介素-6的生成。诸如三磷酸腺苷（ATP）和三磷酸尿苷（UTP）等核苷酸本身也显著增加细胞中白细胞介素-6的生成。进一步证实，ATP可从暴露于SNP30的HaCaT细胞中释放。这些结果支持了ATP在HaCaT细胞SNP30诱导的白细胞介素-6生成中可能发挥的作用。总之，这些数据表明，P2Y11受体也介导人角质形成细胞中SNP30诱导的白细胞介素-6生成，证实ATP-P2Y11嘌呤能信号是导致皮肤炎症性疾病诱导的白细胞介素-6生成的共同途径。
