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Am J Physiol Cell Physiol 289: C264-C276, 2005. First published March 2, 2005; doi:10.1152/ajpcell.00461.2004
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RECEPTORS AND SIGNAL TRANSDUCTION

Mechanism of amyloid peptide induced CCR5 expression in monocytes and its inhibition by siRNA for Egr-1

Ranjit K. Giri,1 Vikram Rajagopal,1 Shweta Shahi,1 Berislav V. Zlokovic,2 and Vijay K. Kalra1

Department of 1Biochemistry & Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California; and 2Center for Aging, University of Rochester, Rochester, New York

Submitted 20 September 2004 ; accepted in final form 16 February 2005

In Alzheimer's disease (AD), one finds increased presence of monocytes/macrophages and activated microglial cells in the brain. Immunohistochemical studies show increased expression of chemokine receptor 5 (CCR5) on reactive microglia associated with amyloid deposits in AD, suggesting that CCR5 may play a role in the regulation of the immune response in AD. In this study, we used peripheral blood monocytes and human monocytic THP-1 cell line as a model of microglia to delineate the cellular signaling mechanism of A{beta}-induced CCR5 expression and the latter's role in the chemotaxis of monocytes. We observed that A{beta} peptides at pathophysiological concentrations (125 nM) increased CCR5 mRNA and cell surface protein expression. The cellular signaling involved activation of c-Raf, ERK-1/ERK-2, and c-Jun NH2-terminal kinase. Analysis of some transcription factors associated with CCR5 promoter revealed that A{beta} increased DNA binding activity of Egr-1 and AP-1. In addition, we show that CCR5 promoter contains an Egr-1 like consensus sequence GCGGGGGTG as demonstrated by 1) electrophoretic mobility shift assay, 2) transfection studies with truncated CCR5 gene promoter construct, and 3) chromatin immunoprecipitation analysis. Moreover, transfection of Egr-1 siRNA, but not of scrambled Egr-1 siRNA, in THP-1 cells resulted in >75% reduction in both A{beta}-mediated CCR5 expression and concomitant chemotaxis to its ligands. We suggest that inhibition of Egr-1 by either Egr-1 siRNA or pharmacological agents may reduce activation of monocytes/microglia and possibly ameliorate the inflammation and progression of AD.

amyloid peptide; chemokine receptor 5; small inhibitory ribonucleic acid


Address for reprint requests and other correspondence: V. K. Kalra, Dept. of Biochemistry & Molecular Biology, HMR-611, USC Keck School of Medicine, Los Angeles, CA 90033 (e-mail: vkalra{at}usc.edu)






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