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Am J Physiol Renal Physiol (December 18, 2001). doi:10.1152/ajprenal.00291.2001
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Articles in PresS, published online ahead of print December 18, 2001
Am J Physiol Renal Physiol, 10.1152/ajprenal.00291.2001
Submitted on September 18, 2001
Accepted on December 31, 1969

CD40 STIMULATES CHEMOKINE PRODUCTION VIA RECRUITMENT OF TRAF6 AND ACTIVATION OF MAP KINASES IN HUMAN PROXIMAL TUBULE CELLS

Li Hongye1 and Edward P Nord1*

1 Medicine/Nephrology, SUNY Stony Brook, Stony Brook, NY, USA

* To whom correspondence should be addressed. E-mail: ENord{at}mail.som.sunysb.edu.

The mechanism of CD40/CD154 induced chemokine production and its potential role in renal inflammatory disease was explored. Human proximal tubule cells maintained in primary culture were used as the experimental model. Using 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 upon engagement by its cognate ligand, CD154, translocated to the cytoplasmic compartment. Engagement of CD40 by CD154 stimulated interleuken-8 (IL-8) and monocyte chemoattractant factor-1 (MCP-1) production, which proceeded via receptor activation of the ERK1/2, SAPK/JNK and p38 MAPK pathways. CD40 ligation also engaged TRAF6 as evidenced by co-localization of the activated receptor with TRAF6 in the cytoplasmic compartment, translocation of both proteins from the insoluble to soluble cell fraction, and co-immunoprecipitation of the two proteins only under ligand stimulated conditions. Furthermore, an antisense ODN 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 upon 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 activities, which in turn stimulate IL-8 and MCP-1 production in these cells.




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