title: The regulatory T cell effector soluble fibrinogen-like protein 2 induces tubular epithelial cell apoptosis in renal transplantation.
abstract: Acute rejection (AR) hinders renal allograft survival. Tubular epithelial cell (TEC) apoptosis contributes to premature graft loss in AR, while the mechanism remains unclear. Soluble fibrinogen-like protein 2 (sFGL2), a novel effector of regulatory T cells (Treg), induces apoptosis to mediate tissue injury. We previously found that serum sFGL2 significantly increased in renal allograft rejection patients. In this study, the role of sFGL2 in AR was further investigated both in vivo and in vitro. The serum level of sFGL2 and the percentage of CD4(+)CD25(+)Foxp3(+) Treg in the peripheral blood were measured in renal allograft recipients with AR or stable renal function (n = 30 per group). The human TEC was stimulated with sFGL2, tumor necrosis factor (TNF)-α, or phosphate buffered saline and investigated for apoptosis in vitro. Apoptosis-associated genes expression in TEC was further assessed. Approval for this study was obtained from the Ethics Committee of Fudan University. Our results showed that the serum level of sFGL2, correlated with Treg in the peripheral blood, was significantly increased in the AR patients. In vitro, sFGL2 remarkably induced TEC apoptosis, with a significant up-regulation of proapoptotic genes, including CASP-3, CASP-8, CASP-9, CASP-10, TRADD, TNFSF10, FADD, FAS, FASLG, BAK1, BAD, BAX, and NF-KB1. However, no significant changes were observed in the expression of antiapoptotic genes, including CARD-18, NAIP, BCL2, IKBKB, and TBK1. Therefore, sFGL2, an effector of Treg, induces TEC apoptosis. Our study suggests that sFGL2 is a potential mediator in the pathogenesis of allograft rejection and provides novel insights into the role of Treg in AR.
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Zitong
authors.initials: Z
authors.lastname: Zhao
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.forename: Tian
authors.initials: T
authors.lastname: Zhao
authors.forename: Linkun
authors.initials: L
authors.lastname: Hu
authors.forename: Ruiming
authors.initials: R
authors.lastname: Rong
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Tongyu
authors.initials: T
authors.lastname: Zhu
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D005340:Fibrinogen / Q000378:metabolism* / Q000494:pharmacology; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects; D008297:Male; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C095202:FGL2 protein, human; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen
keywords: Soluble fibrinogen-like protein 2; apoptosis; regulatory T cells; renal transplantation; tubular epithelial cells