Renal tubular epithelial cell self-injury through Fas/Fas ligand interaction promotes renal allograft injury.
Tubular epithelial cells (TECs) coexpress Fas and Fas ligand (FasL), which could influence renal allograft injury. While TECs can resist apoptosis by Fas antibody, TEC apoptosis by contact with adjacent TECs has not been studied. Fas expression increased in TECs with cytokine treatment (IFN-gamma, TNF-alpha) while abundant FasL levels were not altered. Apoptosis (Annexin-V, DNA fragmentation) occurred in cytokine-treated TECs monolayers from C3H-HeJ mice by 24 h, but was absent in similarly treated TECs from Fas-deficient (lpr) or FasL-mutant (gld) mice, suggesting that 'self injury' occurred through Fas/FasL. Membrane labeling of TECs in cocultures confirmed that FasL-bearing TECs induced apoptosis when in contact with Fas-bearing TECs. Culturing TECs with allogeneic C57BL/6 (H-2b) splenocytes resulted in apoptosis and elimination of C3H-HeJ TECs by 48 h, with enhanced survival and reduced apoptosis using lpr or gld TECs. In a renal allograft model, survival of C57BL/6 recipients was greater (p < 0.05) and renal function improved (p < 0.001) using C3H-lpr or C3H-gld (H-2 k) donor kidneys compared with C3H-HeJ kidneys. These data demonstrate for the first time that cytokine-activated TECs can injure TECs through expression of functional FasL and Fas. We suggest that inhibition of TEC-TEC 'self injury' may be a novel strategy to augment renal allograft survival.
Du
Caigan
C
Department of Medicine, University of Western Ontario, London, ON, Canada. dcaigan@uwo.ca
Jiang
Jifu
J
Guan
Qiunong
Q
Yin
Ziqin
Z
Masterson
Mark
M
Parbtani
Anwar
A
Zhong
Robert
R
Jevnikar
Anthony M
AM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D053938:DNA Fragmentation / Q000502:physiology; D053222:Fas Ligand Protein; D016030:Kidney Transplantation / Q000276:immunology; D007684:Kidney Tubules / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D019014:fas Receptor / Q000276:immunology*
D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor