Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Neuroscience. 2013 Dec 3;253:172-82. doi: 10.1016/j.neuroscience.2013.08.026. Epub 2013 Aug 26.
Cancer pain, particularly bone cancer pain, affects the quality of life of cancer patients, and current treatments are limited. Interleukin (IL)-33, a new member of the IL-1 super family, has been reported to be involved in the modulation of inflammatory pain. However, studies focused on its role in the modulation of cancer pain have been rare. The present study was designed to investigate whether spinal IL-33/ST2 signaling was involved in bone cancer-induced pain in mice. Bone cancer was induced via intra-femoral inoculation of 4T1 mammary carcinoma cells. The mice inoculated with carcinoma cells showed mechanical allodynia, heat hyperalgesia and a reduction in limb use, whereas phosphate-buffered saline or heat-killed cells-injected mice showed no significant difference compared to non-treated mice. The pain hypersensitive behaviors worsened over time and with bone destruction. Both the mRNA and the protein levels of IL-33 and relative cytokines (IL-1β, IL-6, TNF-a) were significantly increased in the spinal cord after the inoculation of carcinoma cells. Intrathecal administration of ST2 antibody to block IL-33/ST2 signaling alleviated pain behaviors in a dose-dependent manner in bone cancer pain mice compared with vehicle-injected mice. Moreover, the ST2(-/-) mice showed a significant amelioration of limb use and heat hyperalgesia compared to wild-type mice. Meanwhile, concentrations of spinal IL-1β, IL-6 and TNF-a in the cancer-bearing ST2(-/-) mice had no significant changes. These data further suggested that IL-33/ST2 signaling played a vital role in cancer pain. Our results provided evidence that IL-33 and its receptor ST2 may be a potential therapeutic target for the treatment of pain in bone cancer patients.
癌症疼痛，尤其是骨癌疼痛，会影响癌症患者的生活质量，而目前的治疗方法有限。白细胞介素（IL）-33 是 IL-1 超家族的新成员，据报道它参与了炎性疼痛的调节。然而，关于其在癌症疼痛调节中的作用的研究还很少。本研究旨在探讨脊髓 IL-33/ST2 信号是否参与了小鼠骨癌引起的疼痛。通过股骨内接种 4T1 乳腺癌细胞诱导骨癌。接种癌细胞的小鼠表现出机械性痛觉过敏、热痛觉过敏和肢体使用减少，而注射磷酸盐缓冲盐水或热灭活细胞的小鼠与未处理的小鼠相比没有明显差异。疼痛敏感行为随着时间的推移和骨破坏而恶化。接种癌细胞后，脊髓中 IL-33 和相关细胞因子（IL-1β、IL-6、TNF-a）的 mRNA 和蛋白水平均显著升高。鞘内给予 ST2 抗体阻断 IL-33/ST2 信号，与载体注射小鼠相比，在骨癌痛小鼠中以剂量依赖的方式减轻疼痛行为。此外，与野生型小鼠相比，ST2(-/-) 小鼠的肢体使用和热痛觉过敏明显改善。同时，骨癌携带的 ST2(-/-) 小鼠脊髓中 IL-1β、IL-6 和 TNF-a 的浓度没有明显变化。这些数据进一步表明，IL-33/ST2 信号在癌症疼痛中起着至关重要的作用。我们的结果提供了证据表明，IL-33 和其受体 ST2 可能是治疗骨癌患者疼痛的潜在治疗靶点。
