The Interleukin-17 G-197A Polymorphism is Associated with Cyclosporine Metabolism and Transplant Rejection in Liver Transplant Recipients

Abstract

Aim: This study aimed to investigate the effect of and mechanism involved in the IL-17 SNP on cyclosporine metabolism and outcomes of liver transplantation (LT). Materials & methods: The IL-17 genotype, IL-17 expression, postoperative outcome and cyclosporine concentration were reviewed in 106 LT recipients. The functional relevance of rs2275913 was evaluated by luciferase assay. Furthermore, L02 cells were treated with IL-17 recombinant protein or/and pregnane X receptor (PXR) knockdown lentiviruses, then the expression of PXR, CYP3A4, CYP3A5 and IL-17R were detected by PCR and western blotting. Result: The significant distribution difference at IL-17 locus G-197A was confirmed between patients with and without rejection (p = 0.035). Patients with acute rejection showed higher IL-17 level than those without rejection. Cyclosporine concentration was associated with the different IL-17 genotype (p < 0.05). Luciferase assay revealed that 197G genotype had higher luciferase activity than that in 197A genotype (p = 0.009). Furthermore, IL-17 recombinant protein remarkably promoted the expressions of PXR, CYP3A4 and CYP3A5 (p < 0.01), but not IL-17R. PXR knockdown significantly inhibited the mRNA levels of CYP3A4 and CYP3A5 but not IL-17R (p < 0.01), while IL-17 recombinant protein had no influence on the expressions of CYP3A4 and CYP3A5 when PXR was downregulated. Conclusion: This study revealed the possible association of IL-17 G-197A with cyclosporine metabolism and transplant rejection after LT, which might be partly related to the upregulations of CYP3A4/5 dependent on PXR.

Keywords::

• cyclosporine
• IL-17
• liver transplantation
• single nucleotide polymorphism

Authors’ contributions

B Sun, W Shi, X Li and G Liu designed the research; B Sun, W Shi, J Gao, Y Guo and J Fan performed the research; B Sun, W Shi, J Gao, Y Guo., J Fan, X Li and G Liu analyzed the data and also wrote the article; and all authors approved the final version.

Financial & competing interests disclosure

This work was supported by the National Natural Science Foundation of China (no. 81403010); the Program for the Key Discipline of Shanghai Jiao Tong University School of Medicine, the Research Fund of Shanghai Jiao Tong University School of Medicine (no. JYY1201) and Outstanding Young Physician Training Program of Shanghai General Hospital (no. 061206). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (no. 81403010); the Program for the Key Discipline of Shanghai Jiao Tong University School of Medicine, the Research Fund of Shanghai Jiao Tong University School of Medicine (no. JYY1201) and Outstanding Young Physician Training Program of Shanghai General Hospital (no. 061206). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.