Syk/BLNK/NF-κB 信号通路促进他克莫司诱导的胰腺损伤，雷帕霉素具有潜在的保护作用。
Syk/BLNK/NF-κB signaling promotes pancreatic injury induced by tacrolimus and potential protective effect from rapamycin.
机构信息
School of Nursing, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
出版信息
Biomed Pharmacother. 2024 Feb;171:116125. doi: 10.1016/j.biopha.2024.116125. Epub 2024 Jan 5.
BACKGROUND
The treatment of tacrolimus-induced post-transplantation diabetes mellitus (PTDM) has become a hot topic to improve the long-term survival of organ transplant patients, however whose pathogenesis has not been fully elucidated. In pancreas, the up-regulation of NF-κB has been reported to stimulate cytokine IL-1β/TNF-α secretion, inducing pancreatic injury, meanwhile other studies have reported the inhibitory effect of rapamycin on NF-κB.
PURPOSE
The aim of this study was to clarify the mechanism of tacrolimus-induced pancreatic injury and to explore the potential effect from small dose of sirolimus.
METHODS
Wistar rats were randomly divided normal control (NC) group, PTDM group, sirolimus intervention (SIR) group. Transcriptomic analysis was used to screen potential mechanism of PTDM. Biochemical index detections were used to test the indicators of pancreatic injury. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot were used to verify the underlying mechanism.
RESULTS
Compared with NC group, the level of insulin was significant reduction (P < 0.01), inversely the level of glucagon was significantly increase (P < 0.01) in PTDM group. Transcriptomic analysis indicated Syk/BLNK/NF-κB signaling was significantly up-regulated in PTDM group. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot verified Syk/BLNK/NF-κB and TNF-α/IL-1β were all significantly increased (P < 0.05 or P < 0.01), demonstrating the mechanism of tacrolimus-induced pancreatic injury via Syk/BLNK/NF-κB signaling. In addition, compared with PTDM group, the levels of weight, FPG, AMY, and GSP in SIR group were significant ameliorative (P < 0.05 or P < 0.01), and the expressions of p-NF-κB, TNF-α/IL-1β in SIR group were significantly reduction (P < 0.05 or P < 0.01), showing Syk/BLNK/NF-κB signaling promoted pancreatic injury induced by tacrolimus and potential protective effect from rapamycin reducing NF-κB.
CONCLUSION
Syk/BLNK/NF-κB signaling promotes pancreatic injury induced by tacrolimus and rapamycin has a potentially protective effect by down-regulating NF-κB. Further validation and clinical studies are needed in the future.
背景
环孢素诱导的移植后糖尿病（PTDM）的治疗已成为提高器官移植患者长期存活率的热门话题，但其发病机制尚未完全阐明。在胰腺中，已报道 NF-κB 的上调可刺激细胞因子 IL-1β/TNF-α 的分泌，从而诱导胰腺损伤，同时其他研究也报道了雷帕霉素对 NF-κB 的抑制作用。
目的
本研究旨在阐明环孢素诱导的胰腺损伤的机制，并探讨小剂量西罗莫司的潜在作用。
方法
将 Wistar 大鼠随机分为正常对照组（NC）、PTDM 组、西罗莫司干预（SIR）组。 转录组分析用于筛选 PTDM 的潜在机制。 生化指标检测用于测试胰腺损伤的指标。 病理染色、免疫组化染色、免疫荧光染色、Western blot 用于验证潜在机制。
结果
与 NC 组相比，PTDM 组胰岛素水平显著降低（P<0.01），而胰高血糖素水平显著升高（P<0.01）。 转录组分析表明，PTDM 组 Syk/BLNK/NF-κB 信号显著上调。 病理染色、免疫组化染色、免疫荧光染色、Western blot 验证了 Syk/BLNK/NF-κB 和 TNF-α/IL-1β均显著增加（P<0.05 或 P<0.01），表明 Syk/BLNK/NF-κB 信号通过 Tacrolimus 诱导胰腺损伤的机制。 此外，与 PTDM 组相比，SIR 组的体重、FPG、AMY 和 GSP 水平均显著改善（P<0.05 或 P<0.01），SIR 组的 p-NF-κB、TNF-α/IL-1β表达水平均显著降低（P<0.05 或 P<0.01），表明 Syk/BLNK/NF-κB 信号促进了 Tacrolimus 诱导的胰腺损伤，雷帕霉素通过下调 NF-κB 具有潜在的保护作用。
结论
Syk/BLNK/NF-κB 信号促进了 Tacrolimus 诱导的胰腺损伤，雷帕霉素通过下调 NF-κB 具有潜在的保护作用。 未来需要进一步验证和临床研究。
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