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

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-12-28 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S496195

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

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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 (P < 0.05 or P < 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 (P < 0.05 or P < 0.01); Inversely, blocking CXCR2 could reverse the expression of p-JAK3/p-STAT3 and tacrolimus-induced hepatotoxicity (P < 0.05 or P < 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.

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CXCR2激活JAK3/STAT3信号通路加重他克莫司相关肝毒性

目的：他克莫司在临床使用过程中可诱发肝毒性，其作用机制尚不清楚，这为他克莫司致肝毒性的防治提出了新的挑战。本研究旨在探讨他克莫司致肝毒性的机制，为药物开发靶点提供参考。方法：采用生化分析、病理染色、免疫荧光染色、免疫组织化学染色、转录组分析、Western blot等方法，探讨他克莫司对基因敲除小鼠和Wistar大鼠肝毒性的作用机制。结果：基因敲除小鼠与野生型小鼠相比，缺乏cxcr2可减轻他克莫司引起的肝毒性（p0.05或p0.01）。Wistar大鼠与对照组相比，CXCL2-CXCR2、JAK3/STAT3信号通路（JAK3、STAT3磷酸化）上调，CIS表达降低，PIM1表达升高，引起肝脏病理改变（P < 0.05或P < 0.01）；相反，阻断CXCR2可逆转P - jak3 / P - stat3的表达和他克莫司诱导的肝毒性（P 0.05或P 0.01）。结论：CXCR2激活JAK3/STAT3信号通路（JAK3和STAT3磷酸化），加重他克莫司肝毒性，同时CIS表达下调，PIM1表达上调。阻断CXCR2可逆转p-JAK3/p-STAT3、CIS、PIM1和他克莫司诱导的肝毒性的表达。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.