PMID- 11997318
OWN - NLM
STAT- MEDLINE
DCOM- 20020531
LR  - 20171116
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 282
IP  - 6
DP  - 2002 Jun
TI  - CD40 ligation stimulates MCP-1 and IL-8 production, TRAF6 recruitment, and MAPK 
      activation in proximal tubule cells.
PG  - F1020-33
AB  - 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 NH(2)-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.
FAU - Li, Hongye
AU  - Li H
AD  - Division of Nephrology, Department of Medicine, School of Medicine, State 
      University of New York at Stony Brook, Stony Brook, New York 11794, USA.
FAU - Nord, Edward P
AU  - Nord EP
LA  - eng
GR  - DK-45605/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (CD40 Antigens)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-8)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (TNF Receptor-Associated Factor 6)
RN  - 147205-72-9 (CD40 Ligand)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - CD40 Antigens/analysis/genetics/*metabolism
MH  - CD40 Ligand/metabolism
MH  - Cell Compartmentation
MH  - Cell Fractionation
MH  - Cells, Cultured
MH  - Chemokine CCL2/*biosynthesis/genetics
MH  - Cytoplasm/chemistry/metabolism
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Flow Cytometry
MH  - Humans
MH  - Immunoblotting
MH  - Interleukin-8/*biosynthesis/genetics
MH  - Kidney Tubules, Proximal/chemistry/cytology/*metabolism
MH  - Macromolecular Substances
MH  - Membrane Microdomains/chemistry/metabolism
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Protein Transport/physiology
MH  - Proteins/*metabolism
MH  - RNA, Messenger/biosynthesis
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/physiology
MH  - TNF Receptor-Associated Factor 6
MH  - Zinc Fingers/physiology
EDAT- 2002/05/09 10:00
MHDA- 2002/06/01 10:01
CRDT- 2002/05/09 10:00
PHST- 2002/05/09 10:00 [pubmed]
PHST- 2002/06/01 10:01 [medline]
PHST- 2002/05/09 10:00 [entrez]
AID - 10.1152/ajprenal.00291.2001 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2002 Jun;282(6):F1020-33. doi: 
      10.1152/ajprenal.00291.2001.