TNFR1‐ and TNFR2‐mediated signaling pathways in human kidney are cell type‐specific and differentially contribute to renal injury
- 27 July 2005
- journal article
- Published by Wiley in The FASEB Journal
- Vol. 19 (12), 1637-1645
- https://doi.org/10.1096/fj.05-3841com
Abstract
In normal kidney, TNFR1 is expressed in glomerular and peritubular capillary EC, and some tubular cells, and colocalizes with inactive apoptosis signal-regulating kinase-1 (ASK1) phosphorylated at serine 967. Biopsies of rejecting or ischemic renal allografts, which show both tubular cell injury and proliferation, display down-regulation of TNFR1 and activation of ASK1 as well as up-regulation of TNFR2 on tubular cells, where it colocalizes with phosphorylated endothelial/epithelial tyrosine kinase (Etk). We have exploited receptor-selective muteins and evaluated phosphorylation of receptor-specific kinases to study TNF responses in situ. In organ culture, a TNFR1-specific mutein changes phosphorylation of ASK1 to threonine 845, indicative of kinase activation. A TNFR2-specific mutein down-regulates TNFR1 in glomerular EC, up-regulates TNFR2 and Etk in tubular cells, and induces phosphorylation of Etk. Wild-type TNF induces TNFR2 and Etk and activates both ASK1 and Etk but does not down-regulate TNFR1. Wild-type TNF and TNFR1-specific mutein trigger tubular cell apoptosis whereas wild-type TNF and TNFR2-specific mutein induce tubular cells to express proliferating cell nuclear antigen. Differential activation of ASK1 and Etk by regulated TNFRs in patient-derived materials provides an explanation for diverse and opposing responses to TNF at distinct sites, and an in situ bioassay of TNFR signaling.—Al-Lamki, R. S., Wang, J., Vandenabeele, P., Bradley, J. A., Thiru, S., Luo, D., Min, W., Pober, J. S., Bradley, J. R. TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury.Keywords
Funding Information
- Medical Research Council
- National Institutes of Health
This publication has 20 references indexed in Scilit:
- AIP1/DAB2IP, a Novel Member of the Ras-GAP Family, Transduces TRAF2-induced ASK1-JNK ActivationOnline Journal of Public Health Informatics, 2004
- p130Cas Couples the Tyrosine Kinase Bmx/Etk with Regulation of the Actin Cytoskeleton and Cell MigrationOnline Journal of Public Health Informatics, 2003
- Etk/Bmx as a Tumor Necrosis Factor Receptor Type 2-Specific Kinase: Role in Endothelial Cell Migration and AngiogenesisMolecular and Cellular Biology, 2002
- TNF receptor-associated factor-2 binding site is involved in TNFR75-dependent enhancement of TNFR55-induced cell deathCell Research, 2001
- The TNF and TNF Receptor Superfamilies: Integrating Mammalian BiologyCell, 2001
- Regulated Commitment of TNF Receptor Signaling: A Molecular Switch for Death or ActivationImmunity, 1999
- A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptorCell, 1994
- Human tumor necrosis factor mutants with preferential binding to and activity on either the R55 or R75 receptorJBIC Journal of Biological Inorganic Chemistry, 1994
- Human TNF mutants with selective activity on the p55 receptorNature, 1993
- Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.The Journal of cell biology, 1992