The Journal of Experimental Medicine
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Published online 20 November 2000.
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© The Rockefeller University Press, 0022-1007/2000/11/1501/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 10, November 20, 2000 1501-1508

Original Article

Natural Proteolytic Processing of Hemofiltrate Cc Chemokine 1 Generates a Potent Cc Chemokine Receptor (Ccr)1 and Ccr5 Agonist with Anti-HIV Properties

Michel Detheuxa, Ludger Ständkerb, Jalal Vakilic, Jan Münchd, Ulf Forssmannb,e, Knut Adermannb, Stefan Pöhlmannd, Gilbert Vassartc, Frank Kirchhoffd, Marc Parmentierc, and Wolf-Georg Forssmannb

a From Euroscreen S.A., B-1070 Brussels, Belgium
b The Lower Saxony Institute for Peptide Research (IPF), D-30625 Hannover, Germany
c Institute of Interdisciplinary Research, Université Libre de Bruxelles, B-1070 Brussels, Belgium
d Institute for Clinical and Molecular Virology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
e Department of Urology, Johannes Gutenberg University, 55131 Mainz, Germany
IRIBHN, ULB, Campus Erasme, 808 Route de Lennik, B-1070 Bruxelles, Belgium.32-2-555-46-5532-2-555-41-71

Hemofiltrate CC chemokine (HCC)-1 is a recently described human chemokine that is constitutively expressed in numerous tissues and is present at high concentrations in normal plasma. Using a cell line expressing CC chemokine receptor (CCR)5 as a bioassay, we isolated from human hemofiltrate an HCC-1 variant lacking the first eight amino acids. HCC-1[9–74] was a potent agonist of CCR1, CCR3, and CCR5 and promoted calcium flux and chemotaxis of T lymphoblasts, monocytes, and eosinophils. It also blocked entry of HIV-1 strains using CCR5 as coreceptor. Limited tryptic digestion of HCC-1 generated the active variant. Conditioned media from several tumor cell lines activated HCC-1 with a high efficiency, and this activity could be inhibited by serine protease inhibitors. Our results indicate that HCC-1 represents a nonfunctional precursor that can be rapidly converted to the active chemokine by proteolytic processing. This process represents an additional mechanism by which tumor cells might generate chemoattractant molecules and recruit inflammatory cells. It might also affect HIV-1 replication in infected individuals and play an important role in AIDS pathogenesis.

Key Words: receptors, CCR5 • chemokines, CC • biological assay • endopeptidase • HIV

Abbreviations used in this paper: HCC, hemofiltrate CC chemokine; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; RANTES, regulated upon activation, normal T cell expressed and secreted.

M. Detheux, L. Ständker, and J. Vakili contributed equally to this work.

© 2000 The Rockefeller University Press


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