TL1A both promotes and protects from renal inflammation and injury.
Death receptor 3 (DR3), a member of the TNF receptor (TNFR) superfamily, is induced in human renal tubular epithelial cells (TEC) in response to injury. This study examined the expression and actions of TL1A, the principal ligand for DR3. In histologically normal tissue from biopsy or nephrectomy specimens of renal allografts, TL1A mRNA and protein were expressed in vascular endothelial cells but not in TEC. In specimens of acute or antibody-mediated allograft rejection, vascular endothelial cells and infiltrating leukocytes expressed increased TL1A mRNA and protein, but TEC expressed TL1A protein without mRNA, consistent with uptake of exogenous ligand. Addition of TL1A to organ cultures of human or mouse kidney caused activation of NF-kappaB, expression of TNFR2, activation of caspase-3, and apoptosis in TEC. Inhibition of NF-kappaB activation increased TL1A-mediated caspase-3 activation and apoptosis of TEC, but it did not reduce the induction of TNFR2. In organ culture of DR3-deficient mouse kidneys, addition of TL1A induced TNFR2 but did not activate NF-kappaB and did not increase apoptosis of TEC. These data suggest that TL1A may contribute to renal inflammation and injury through DR3-mediated activation of NF-kappaB and caspase-3, respectively, but that an unidentified receptor may mediate the NF-kappaB-independent induction of TNFR2 in TEC.
Al-Lamki
Rafia S
RS
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. rsma2@hermes.cam.ac.uk
Wang
Jun
J
Tolkovsky
Aviva M
AM
Bradley
J Andrew
JA
Griffin
Jules L
JL
Thiru
Sathia
S
Wang
Eddie C Y
EC
Bolton
Eleanor
E
Min
Wang
W
Moore
Paul
P
Pober
Jordan S
JS
Bradley
John R
JR
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001706:Biopsy; D053148:Caspase 3 / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D016030:Kidney Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
D016328:NF-kappa B; D012333:RNA, Messenger; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047889:Receptors, Tumor Necrosis Factor, Type II; C506033:TNFRSF25 protein, human; C117026:TNFSF15 protein, human; C506034:Tnfrsf25 protein, mouse; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D053148:Caspase 3