Bo Sun1,2, Junwei Gao1, Weifeng Shi1, Yankun Guo1, Junwei Fan3, Jigang Zhang1, Xiaoyu Li4, Gaolin Liu1. 1. Department of Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. 2. Shanghai Center for Drug Evaluation and Inspection, Shanghai, PR China. 3. Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. 4. Department of pharmacy, Zhongshan Hospital, Fudan University, Shanghai, PR China.
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.
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.
Entities:
Keywords:
IL-17; liver transplantation; single nucleotide polymorphism; cyclosporine
Authors: Tomislav Kelava; Petra Turcic; Antonio Markotic; Ana Ostojic; Dino Sisl; Anna Mrzljak Journal: World J Gastroenterol Date: 2020-03-28 Impact factor: 5.742