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

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.