The interleukin (IL)-6/IL-6 receptor-α (IL-6Rα)/signal transduction and activation of the transcription 3 (STAT3) pathway plays an important role in inflammation. Anti-human IL-6Rα blockade by tocilizumab (TCZ) has been used in pig-to-baboon organ xenotransplant models, but whether it is beneficial remains uncertain. After xenotransplant, there were significant increases in both baboon and pig IL-6 in the baboon serum, especially in baboons that received TCZ before xenotransplant. In vitro observations demonstrated that human, baboon, and pig IL-6 can activate the IL-6/IL-6Rα/STAT3 pathway in human, baboon, and pig cells, respectively. Activation of the IL-6/IL-6Rα/STAT3 pathway was blocked by TCZ in human and baboon cells but not in pig cells (ie, pig IL-6R). Siltuximab (human IL-6 inhibitor) bound to both human and baboon, but not pig, IL-6 and suppressed activation of the IL-6/IL-6Rα/STAT3 pathway. These results indicate that TCZ and siltuximab do not cross-react with pig IL-6R and pig IL-6, respectively. Rapamycin partially inhibited human, baboon, and pig IL-6/IL-6Rα/STAT3 pathways and suppressed inflammatory gene expression. TCZ treatment increased serum IL-6 because it could no longer bind to baboon IL-6Rα. We suggest that increased serum IL-6 may be detrimental to the pig xenograft because it is likely to bind to pig IL-6R, resulting in activation of pig cells.

中文翻译：

---

白细胞介素 6 受体阻断剂（托珠单抗）对猪狒狒器官异种移植有利还是有害？

白细胞介素 (IL)-6/IL-6 受体-α (IL-6Rα)/信号转导和激活转录 3 (STAT3) 通路在炎症中起重要作用。托珠单抗 (TCZ) 的抗人 IL-6Rα 阻断已用于猪狒狒器官异种移植模型，但它是否有益仍不确定。异种移植后，狒狒血清中的狒狒和猪 IL-6 均显着增加，尤其是在异种移植前接受 TCZ 的狒狒中。体外观察表明，人、狒狒和猪 IL-6 可分别激活人、狒狒和猪细胞中的 IL-6/IL-6Rα/STAT3 通路。IL-6/IL-6Rα/STAT3 通路的激活在人和狒狒细胞中被 TCZ 阻断，但在猪细胞（即猪 IL-6R）中没有。Siltuximab（人 IL-6 抑制剂）与人类和狒狒结合，但不与猪结合，IL-6 并抑制 IL-6/IL-6Rα/STAT3 通路的激活。这些结果表明 TCZ 和西妥昔单抗分别不与猪 IL-6R 和猪 IL-6 发生交叉反应。雷帕霉素部分抑制人、狒狒和猪的 IL-6/IL-6Rα/STAT3 通路并抑制炎症基因表达。TCZ 治疗增加了血清 IL-6，因为它不再与狒狒 IL-6Rα 结合。我们认为升高的血清 IL-6 可能对猪异种移植物有害，因为它可能与猪 IL-6R 结合，导致猪细胞活化。TCZ 治疗增加了血清 IL-6，因为它不再与狒狒 IL-6Rα 结合。我们认为升高的血清 IL-6 可能对猪异种移植物有害，因为它可能与猪 IL-6R 结合，导致猪细胞活化。TCZ 治疗增加了血清 IL-6，因为它不再与狒狒 IL-6Rα 结合。我们认为升高的血清 IL-6 可能对猪异种移植物有害，因为它可能与猪 IL-6R 结合，导致猪细胞活化。