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CXCR2激活的JAK3/STAT3信号通路加剧他克莫司相关肝毒性

CXCR2 Activated JAK3/STAT3 Signaling Pathway Exacerbating Hepatotoxicity Associated with Tacrolimus.

作者信息

Chen Xiao, Hu Ke, Zhang Yue, He Su-Mei, Wang Dong-Dong

机构信息

School of Nursing, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China.

Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China.

出版信息

Drug Des Devel Ther. 2024 Dec 28;18:6331-6344. doi: 10.2147/DDDT.S496195. eCollection 2024.

DOI:10.2147/DDDT.S496195
PMID:39749191
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11693940/
Abstract

PURPOSE

Tacrolimus could induce hepatotoxicity during clinical use, and the mechanism was still unclear, which posed new challenge for the prevention and treatment of tacrolimus-induced hepatotoxicity. The aim of this study was to investigate the mechanism of tacrolimus-induced hepatotoxicity and provide reference for drug development target.

METHODS

In this study, biochemical analysis, pathological staining, immunofluorescent staining, immunohistochemical staining, transcriptomic analysis, Western blotting was used to investigate the mechanism of tacrolimus-induced hepatotoxicity in gene knockout mice and Wistar rats.

RESULTS

In gene knockout mice, compared to wild-type mice, CXCR2-deficiency alleviated tacrolimus-induced hepatotoxicity ( 0.05 or 0.01). In Wistar rats, compared to control group, CXCL2-CXCR2, JAK3/STAT3 signaling pathway (phosphorylation of JAK3 and STAT3) were up-regulated, the expression of CIS was lowered and the expression of PIM1 was raised, inducing liver pathological change ( 0.05 or 0.01); Inversely, blocking CXCR2 could reverse the expression of p-JAK3/p-STAT3 and tacrolimus-induced hepatotoxicity ( 0.05 or 0.01).

CONCLUSION

CXCR2 activated JAK3/STAT3 signaling pathway (phosphorylation of JAK3 and STAT3) exacerbating hepatotoxicity associated with tacrolimus, meanwhile the expression of CIS was down-regulated, the expression of PIM1 was up-regulated. Blocking CXCR2 could reverse the expression of p-JAK3/p-STAT3, CIS, PIM1, and tacrolimus-induced hepatotoxicity.

摘要

目的

他克莫司在临床使用过程中可诱发肝毒性，但其机制尚不清楚，这给他克莫司所致肝毒性的防治带来了新挑战。本研究旨在探讨他克莫司诱发肝毒性的机制，为药物研发靶点提供参考。

方法

本研究采用生化分析、病理染色、免疫荧光染色、免疫组化染色、转录组分析、蛋白质免疫印迹法，在基因敲除小鼠和Wistar大鼠中研究他克莫司诱发肝毒性的机制。

结果

在基因敲除小鼠中，与野生型小鼠相比，CXCR2基因缺陷减轻了他克莫司诱发的肝毒性（P<0.05或P<0.01）。在Wistar大鼠中，与对照组相比，CXCL2-CXCR2、JAK3/STAT3信号通路（JAK3和STAT3磷酸化）上调，CIS表达降低，PIM1表达升高，诱发肝脏病理改变（P<0.05或P<0.01）；相反，阻断CXCR2可逆转p-JAK3/p-STAT3的表达及他克莫司诱发的肝毒性（P<0.05或P<0.01）。

结论

CXCR2激活JAK3/STAT3信号通路（JAK3和STAT3磷酸化）加重了与他克莫司相关的肝毒性，同时CIS表达下调，PIM1表达上调。阻断CXCR2可逆转p-JAK3/p-STAT3、CIS、PIM1的表达及他克莫司诱发的肝毒性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/3e61f9790d0e/DDDT-18-6331-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/7b9f3d6ef403/DDDT-18-6331-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/ac94698c7d17/DDDT-18-6331-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/9ac6ca998215/DDDT-18-6331-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/9e1cf02b414b/DDDT-18-6331-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/230209ed7af3/DDDT-18-6331-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/6717dd6c25a0/DDDT-18-6331-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/3a9df8dd6e73/DDDT-18-6331-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/7cb7dec8cd37/DDDT-18-6331-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/3e61f9790d0e/DDDT-18-6331-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/7b9f3d6ef403/DDDT-18-6331-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/ac94698c7d17/DDDT-18-6331-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/9ac6ca998215/DDDT-18-6331-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/9e1cf02b414b/DDDT-18-6331-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/230209ed7af3/DDDT-18-6331-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/6717dd6c25a0/DDDT-18-6331-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/3a9df8dd6e73/DDDT-18-6331-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/7cb7dec8cd37/DDDT-18-6331-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac32/11693940/3e61f9790d0e/DDDT-18-6331-g0009.jpg

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