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1 Division of Nephrology, Department of Medicine School of Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA
* To whom correspondence should be addressed. E-mail: lihy66{at}yahoo.com.
The role of caveolae in CD40/CD154 activation of pro-inflammatory chemokines and their potential role in renal inflammatory disease was explored in primary cultures of human renal proximal tubule epithelial cells. With the use of a cell fractionation assay, caveolin-1 (Cav-1), the defining structural protein of caveolae, was detected exclusively in the cell membrane (detergent-insoluble) component of resting and CD40-activated cells. In the unstimulated condition, CD40 was associated with Cav-1, and upon activation of the receptor by its cognate ligand CD154, CD40 disassociated from Cav-1. Other previously identified components of the CD40 signaling pathway, namely stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK), p38, and extracellular signal-related kinase (ERK 1/2) mitogen activated protein kinases (MAPKs), but not tumor necrosis factor receptoractivating factor 6 (TRAF6) were also present within caveolae, and dissociated from this structure upon ligation of the CD40 receptor. Disruption of caveolae with filipin diminished CD40-mediated MAPK activation and blunted downstream monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) production. Likewise, dislodgment of signaling proteins from their scaffolding with a peptide targeted to the Cav-1 scaffolding domain (CSD), resulted in blunted MAPK activation and augmented IL-8 and MCP-1 production. In contrast, epidermal growth factor (EGF) mediated tyrosine phosphorylation of the EGF receptor (EGFR) and activation of ERK 1/2 was not interrupted by the peptide. We conclude that in human renal proximal tubule epithelial cells, CD40 and its downstream MAPK signaling proteins are located in membrane rafts and that disruption of caveolae or dislodgment of signaling proteins from the CSD, diminishes MAPK activation and IL-8 and MCP-1 production in these cells.
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