HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 15, 9513-9522, April 11, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/15/9513    most recent M706239200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mydel, P. Articles by Senior, R. M. Search for Related Content PubMed PubMed Citation Articles by Mydel, P. Articles by Senior, R. M. Social Bookmarking                      What's this?

Neutrophil Elastase Cleaves Laminin-332 (Laminin-5) Generating Peptides That Are Chemotactic for Neutrophils^*

Piotr Mydel, J. Michael Shipley, Tracy L. Adair-Kirk, Diane G. Kelley, Thomas J. Broekelmann, Robert P. Mecham, and Robert M. Senior¹

From the Department of Medicine, Division of Pulmonary and Critical Care Medicine, and the Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri 63110

Proteolytic processing of laminin-332 by matrix metalloproteinase (MMP)-2 and MMP-14 has been shown to yield fragments that are promigratory for epithelial cells. During acute and chronic inflammation, proteases are elaborated by neutrophils and macrophages that can degrade basement membranes. We investigated the susceptibility of laminin-332 to degradation by the following neutrophil and macrophage proteases: neutrophil elastase (NE), cathepsin G, proteinase-3, and MMPs-2, -8, -9, and -12. Protease-specific differences were seen in the capacity to cleave the individual chains of laminin-332. NE and MMP-12 showed the greatest activity toward the 2 chain, generating a fragment similar in size to the 2x fragment generated by MMP-2. The digestion pattern of laminin-332 by degranulated neutrophils was nearly identical to that generated with NE alone. Digestion by supernatants of degranulated neutrophils was blocked by an inhibitor of NE, and NE-deficient neutrophils were essentially unable to digest laminin-332, suggesting that NE is the major neutrophil-derived protease that degrades laminin-332. In vivo, laminin 2 fragments were found in the bronchoalveolar lavage fluid of wild-type mice treated with lipopolysaccharide, whereas that obtained from NE-deficient mice showed a different cleavage pattern. In addition, NE cleaved a synthetic peptide derived from the region of human laminin 2 containing the MMP-2 cleavage site, suggesting that NE may generate laminin-332 fragments that are also promigratory. Both laminin-332 fragments generated by NE digestion and NE-digested laminin 2 peptide were found to be chemotactic for neutrophils. Collectively, these data suggest that degradation of laminin-332 by NE generates fragments with important biological activities.

Received for publication, July 30, 2007 , and in revised form, December 14, 2007.

^* This work was supported by National Institutes of Health NHLBI Grant HL29594 and the Alan A. and Edith L. Wolff Charitable Trust/Barnes-Jewish Hospital Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Washington University School of Medicine, Campus Box 8052, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-454-7113; Fax: 314-454-8605; E-mail: rsenior{at}im.wustl.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?