title: Soluble FGL2 induced by tumor necrosis factor-α and interferon-γ in CD4+ T cells through MAPK pathway in human renal allograft acute rejection.
abstract: BACKGROUND
  Acute rejection (AR), initiated by alloreactive CD4(+) T cells, hampers allograft survival. Soluble fibrinogen-like protein 2 (sFGL2) is a novel effector of CD4(+) T cells. We previously found that serum sFGL2 significantly increased in renal allograft recipients with AR. In this study, sFGL2 secretion by CD4(+) T cells and its mechanism were further explored both in vivo and in vitro.
  
  
  METHODS
  Forty cases of living-related renal transplant recipients with biopsy-proven AR or stable renal function were collected and detected serum sFGL2, tumor necrosis factor (TNF)-α and interferon (IFN)-γ, and peripheral CD4(+) T cells. In vitro, the isolated human CD4(+) T cells were stimulated by TNF-α or IFN-γ. sFGL2 in the supernatant and mitogen-activated protein kinase (MAPK) proteins in the CD4(+) T cells were investigated. Approval for this study was obtained from the Ethics Committee of Fudan University.
  
  
  RESULTS
  sFGL2, TNF-α, IFN-γ, and CD4(+) T cells were significantly increased in the peripheral blood of renal allograft recipients with AR. Stimulation with 1000 U/mL TNF-α or 62.5 U/mL IFN-γ for 48 h provided an optimal condition for CD4(+) T cells to secrete sFGL2 in vitro. Phosphorylated (p-) c-Jun N-terminal kinase was remarkably upregulated in the activated CD4(+) T cells, whereas no significant changes were found in p-p38 MAPK or p-ERK1/2 expression. Furthermore, inhibition of c-Jun N-terminal kinase significantly reduced sFGL2 secretion by CD4(+) T cells.
  
  
  CONCLUSIONS
  sFGL2 secretion by CD4(+) T cells can be induced with TNF-α and IFN-γ stimulation through MAPK signaling in renal allograft AR. Our study suggests that sFGL2 is a potential mediator in the pathogenesis of allograft rejection.
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
authors.forename: Zitong
authors.initials: Z
authors.lastname: Zhao
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.forename: Tian
authors.initials: T
authors.lastname: Zhao
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.forename: Linkun
authors.initials: L
authors.lastname: Hu
authors.forename: Duojiao
authors.initials: D
authors.lastname: Wu
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; D064591:Allografts; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D006084:Graft Rejection / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D016030:Kidney Transplantation; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C095202:FGL2 protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005340:Fibrinogen; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: CD4(+) T cells; MAPK pathway; Renal allograft rejection; Soluble FGL2; TNF-α and IFN-γ