| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Division of Nephrology, Department of Medicine, School of Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794
The mechanism of CD40/CD154-induced chemokine production and its potential role in renal inflammatory disease were explored. Human proximal tubule cells maintained in primary culture were used as the experimental model. With the use of immunocytochemistry, confocal microscopy, and a cell fractionation assay, the CD40 receptor was found to be expressed in the cell membrane of the epithelial cell, and, on engagement by CD154, its cognate ligand, translocated to the cytoplasmic compartment. Engagement of CD40 by CD154 stimulated interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production, which proceeded via receptor activation of the extracellular signal-regulated kinase (ERK)1/2, stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) pathways. CD40 ligation also engaged tumor necrosis factor receptor-activating factor 6 (TRAF6), as evidenced by colocalization of the activated receptor with TRAF6 in the cytoplasmic compartment, translocation of both proteins from the insoluble to the soluble cell fraction, and coimmunoprecipitation of the two proteins only under ligand-stimulated conditions. Furthermore, an antisense oligodeoxyribonucleotide targeted against TRAF6 mRNA blunted p38 and SAPK/JNK but not ERK1/2 MAPK activities, as well as IL-8 and MCP-1 production, arguing that TRAF6 is an upstream activator. The zinc chelator TPEN, but not the calcium chelator BAPTA, obliterated CD154-evoked MAPK activity and chemokine production, providing indirect evidence for protein-protein interactions playing a critical role in CD40 signaling in these cells. We conclude that in human proximal tubule cells, CD40 and TRAF6 reside in separate low-density, detergent-insoluble membrane microdomains, or rafts, and on activation translocate and associate with one another probably via zinc-finger domains in the soluble or cytoplasmic compartment. TRAF6, in turn, activates SAPK/JNK and p38 MAPK phosphorylation, which in turn stimulates IL-8 and MCP-1 production in these cells.
chemokines; interstitial inflammation; signaling pathways; colocalization; rafts; monocyte chemoattractant protein-1; tumor necrosis factor receptor-activating factor 6; interleukin-8; mitogen-activated protein kinase
This article has been cited by other articles:
|
|
 |
|
  V. W.S. Lee, X. Qin, Y. Wang, G. Zheng, Y. Wang, Y. Wang, J. Ince, T. K. Tan, L. K. Kairaitis, S. I. Alexander, et al. The CD40-CD154 co-stimulation pathway mediates innate immune injury in adriamycin nephrosis Nephrol. Dial. Transplant., November 4, 2009; (2009) gfp569v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Li and E. P. Nord IL-8 amplifies CD40/CD154-mediated ICAM-1 production via the CXCR-1 receptor and p38-MAPK pathway in human renal proximal tubule cells Am J Physiol Renal Physiol, February 1, 2009; 296(2): F438 - F445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Hung, C.-T. Chang, Y.-C. Tian, M.-S. Wu, C.-C. Yu, M.-J. Pan, A. Vandewalle, and C.-W. Yang Leptospiral membrane proteins stimulate pro-inflammatory chemokines secretion by renal tubule epithelial cells through toll-like receptor 2 and p38 mitogen activated protein kinase Nephrol. Dial. Transplant., April 1, 2006; 21(4): 898 - 910. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pontrelli, M. Ursi, E. Ranieri, C. Capobianco, F. P. Schena, L. Gesualdo, and G. Grandaliano CD40L Proinflammatory and Profibrotic Effects on Proximal Tubular Epithelial Cells: Role of NF-{kappa}B and Lyn J. Am. Soc. Nephrol., March 1, 2006; 17(3): 627 - 636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li and E. P. Nord CD40/CD154 ligation induces mononuclear cell adhesion to human renal proximal tubule cells via increased ICAM-1 expression Am J Physiol Renal Physiol, July 1, 2005; 289(1): F145 - F153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. de Haij, A. C. Bakker, R. N. van der Geest, G. Haegeman, W. Vanden Berghe, J. Aarbiou, M. R. Daha, and C. van Kooten NF-{kappa}B Mediated IL-6 Production by Renal Epithelial Cells Is Regulated by C-Jun NH2-Terminal Kinase J. Am. Soc. Nephrol., June 1, 2005; 16(6): 1603 - 1611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Fox, Q. Yang, L. A. Cupples, C.-Y. Guo, M. G. Larson, E. P. Leip, P. W.F. Wilson, and D. Levy Genomewide Linkage Analysis to Serum Creatinine, GFR, and Creatinine Clearance in a Community-Based Population: The Framingham Heart Study J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2457 - 2461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. H. Lapchak, M. Melter, S. Pal, J. A. Flaxenburg, C. Geehan, M. H. Frank, D. Mukhopadhyay, and D. M. Briscoe CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island Am J Physiol Renal Physiol, September 1, 2004; 287(3): F512 - F520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li and E. P. Nord Functional caveolae are a prerequisite for CD40 signaling in human renal proximal tubule cells Am J Physiol Renal Physiol, April 1, 2004; 286(4): F711 - F719. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
