Exposure of cryptic domains in the α1-chain of laminin-1 by elastase stimulates macrophages urokinase and matrix metalloproteinase-9 expression

Document Type

Journal Article

Publication Date

4-19-2002

Journal

Journal of Biological Chemistry

Volume

277

Issue

16

DOI

10.1074/jbc.M111290200

Abstract

Degradation of the extracellular matrix leads to the release of fragments, which elicit biological responses distinct from intact molecules. We have reported that α1: Ser2091-Arg2108 a peptide derived from the al-chain of laminin-1, triggers protein kinase C-dependent activation of MAPKerk1/2, leading to the up-regulation of macrophage urokinase type plasminogen activator and matrix metalloproteinase (MMP)-9 expression. Since intact laminin-1 failed to trigger these events, we hypothesized that α1: Ser2091-Arg2108 is cryptic or assumes a conformation not recognized by macrophages. Here we demonstrate that elastase cleavage of laminin-1 generates fragments, which stimulate proteinase expression by RAW264.7 macrophages and peritoneal macrophages. In contrast, fragments generated by MMP-2, MMP-7, or plasmin had no effect on macrophage proteinase expression. Elastase-generated laminin-1 fragments were fractionated by heparin-Sepharose chromatography. Heparin-binding fragments stimulated macrophages' proteinase expression severalfold greater than nonbinding fragments. The heparin binding fragments reacted with antibodies directed against regions of the α1-chain including α1: Ser2091-Arg2108 and the globular domain. A peptide from the first loop of the globular domain (α1: Ser2179-Ser2198) triggered the phosphorylation of MAPKerk1/2 and stimulated the expression of macrophage urokinase type plasminogen activator and MMP-9. Moreover, a heparin-binding fraction isolated from an aortic aneurysm contained fragments of α1-chain and stimulated macrophages' proteinase expression. Based on these data, we conclude that cryptic domains in the COOH-terminal portion of the α1-chain of laminin are exposed by proteolysis and stimulate macrophages' proteinase expression.

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