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J Biol Chem. 2002 May 3;277(18):15677-89. Epub 2002 Feb 26.

Leukocyte elastase negatively regulates Stromal cell-derived factor-1 (SDF-1)/CXCR4 binding and functions by amino-terminal processing of SDF-1 and CXCR4.

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1
Unité d'Immunologie Virale, INSERM U485 de l'Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.

Abstract

Activation of CXCR4 by the CXC chemokine stromal cell-derived factor-1 (SDF-1) requires interaction of the amino-terminal domains of both molecules. We report that proteinases released from either mononucleated blood cells or polymorphonuclear neutrophils degranulated by inflammatory stimuli generate an SDF-1 fragment that is deleted from amino-terminal residues Lys(1)-Pro(2)-Val(3), as characterized by mass spectrometry analysis. The proteolyzed chemokine fails to induce agonistic functions and is unable to prevent the fusogenic capacity of CXCR4-tropic human immunodeficiency viruses. Furthermore, we observed that exposure of CXCR4-expressing cells to leukocyte proteinases results in the proteolysis of the extracellular amino-terminal domain of the receptor, as assessed by flow cytometry analysis and electrophoretic separation of immunoprecipitated CXCR4. Blockade of SDF-1 and CXCR4 proteolysis by the specific leukocyte elastase inhibitor, N-methoxysuccinyl-alanine-alanine-proline-valine-chloromethyl ketone, identified elastase as the major enzyme among leukocyte-secreted proteinases that accounts for inactivation of both SDF-1 and CXCR4. Indeed, purified leukocyte elastase generated in either SDF-1 or CXCR4 a pattern of cleavage indistinguishable from that observed with leukocyte-secreted proteinases. Our findings suggest that elastase-mediated proteolysis of SDF-1/CXCR4 is part of a mechanism regulating their biological functions in both homeostatic and pathologic processes.

PMID:
11867624
DOI:
10.1074/jbc.M111388200
[Indexed for MEDLINE]
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