Xiao Chen,1,* Ke Hu,2,* Yue Zhang,2 Su-Mei He,3 Dong-Dong Wang2 

1School of Nursing, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 2Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 3Department of Pharmacy, Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu, 215153, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Su-Mei He, Department of Pharmacy, Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu, 215153, People’s Republic of China, Email hehe8204@163.com Dong-Dong Wang, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China, Email 13852029591@163.com

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.

Keywords: CXCR2, JAK3/STAT3 signaling pathway, hepatotoxicity, tacrolimus, CIS, PIM1