Janus kinase inhibitor ruxolitinib blocks thymic regeneration after acute thymus injury
Janus kinase inhibitor ruxolitinib blocks thymic regeneration after acute thymus injury
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Janus 激酶抑制剂鲁索替尼可阻断急性胸腺损伤后的胸腺再生
DOI：
10.1016/j.bcp.2019.113712
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发表时间：
2020-01-01
影响因子：
5.8
通讯作者：
Xu, Kailin
中科院分区：
文献类型：
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作者：
Li, Lingling;Shang, Longmei;Xu, Kailin
胸腺上皮细胞 (TEC) 对于 T 细胞的产生至关重要。包括细胞毒性药物和电离辐射在内的癌症疗法会损害 TEC，导致 T 细胞产生和功能异常。幸运的是，TEC 在受伤后可以再生。 Janus 激酶 (Jak) 通路对于支持 TEC 的生存非常重要。 Jak 抑制剂用于治疗癌症和免疫疾病。 Jak 抑制剂对 TEC 恢复的影响尚不清楚。我们通过电离辐射诱导小鼠急性胸腺损伤，并评估鲁索替尼对胸腺再生的影响。我们还测试了鲁索替尼是否影响体外 TEC 的增殖。急性损伤后胸腺细胞的恢复增加与 TEC 相关生长因子的上调有关，包括角质形成细胞生长因子 (Kgf)、表皮生长因子 (Egf)、胰岛素样生长因子 1 (Igf1) 和 NF-κ B 配体受体激活剂 (Rankl)。给予鲁索替尼可降低 TEC 上这些生长因子的受体水平，并阻止受损胸腺中生长因子诱导的胸腺细胞恢复。 Ruxolitinib 还在体外阻断生长因子诱导的 TEC 增殖。当胸腺损伤后立即给予鲁索替尼时，胸腺再生受到抑制，但 1 周后给予则不会受到抑制。这些数据可能对鲁索替尼在临床实践中的使用方式产生影响。
Thymic epithelial cells (TECs) are crucial for the production of T-cells. Cancer therapies including cytotoxic drugs and ionizing radiations damage TECs resulting in abnormal T-cell production and function. Fortunately, TECs can regenerate after injury. The Janus kinase (Jak) pathway is important in supporting survival of TECs. Jak inhibitors are used to treat cancer and immune disorders. The impact of Jak inhibitors on recovery of TECs is unknown. We induced acute thymus injury in mice by using ionizing radiation and evaluated the impact of ruxolitinib on thymus regeneration. We also tested if ruxolitinib affected proliferation of TECs in vitro. An increase was observed in the recovery of thymus cells after acute injury in association with up-regulation of TEC-related growth factors including keratinocyte growth factor (Kgf), epidermal growth factor (Egf), insulin-like growth factor 1 (Igf1) and receptor activator of NF-kappa B ligand (Rankl). Giving ruxolitinib decreased levels of receptors of these growth factors on TECs and blocked growth factor-induced recovery of thymus cells in damaged thymii. Ruxolitinib also blocked growth factors-induced proliferation of TECs in vitro. Thymus regeneration was inhibited when ruxolitinib was given immediately after thymus injury but not when it was given 1 week later. These data may have implications for how ruxolitinib is used in clinical practices.