The Journal of Experimental Medicine
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Published online 8 September 2003 doi:10.1084/jem.20030626
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© Rockefeller University Press, 0022-1007/2003/9/925 $5.00
The Journal of Experimental Medicine, Volume 198, Number 6, 925-935

Matrilysin-dependent Elastolysis by Human Macrophages

Sergey Filippov1, Ingrid Caras2, Richard Murray2, Lynn M. Matrisian3, Harold A. Chapman, Jr.4, Steven Shapiro5 and Stephen J. Weiss1

1 University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
2 Eos Biotechnology, Inc., South San Francisco, CA 94080
3 Vanderbilt University, Nashville, TN 37232
4 University of California San Francisco, San Francisco, CA 94143
5 Harvard University, Boston, MA 02115

Address correspondence to Stephen J. Weiss, University of Michigan Comprehensive Cancer Center, 5220 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109. Phone: (734) 764-0030; Fax: (734) 764-0101; email: sjweiss{at}umich.edu

Human macrophages found in juxtaposition to fragmented elastin in vivo express the elastolytic matrix metalloproteinases (MMPs) progelatinase B, prometalloelastase, and promatrilysin. Though MMPs can degrade a range of extracellular matrix components, increasing evidence suggests that preferred targets in vivo include nonmatrix substrates such as chemokines and growth factors. Hence, the means by which MMPs participate in elastin turnover remain undefined as does the identity of the elastolysins. Herein, human macrophage cultures have been established that express a complement of elastolytic proteinases similar, if not identical, to that found in vivo. Under plasminogen-free conditions, macrophages preferentially use metalloelastase to mediate elastolysis via a process that deposits active enzyme on elastin surfaces. By contrast, in the presence of plasminogen, human macrophages up-regulate proteolysis 10-fold by processing promatrilysin to an active elastolysin via a urokinase-type plasminogen activator-dependent pathway. Matrilysin-deficient human macrophages fail to mediate an elastolytic response despite the continued expression of gelatinase B and metalloelastase. Thus, acting in concert with cosecreted cysteine proteinases whose activities are constrained to sites of macrophage-elastin contact (Punturieri, A., S. Filippov, E. Allen, I. Caras, R. Murray, V. Reddy, and S.J. Weiss. 2000. J. Exp. Med. 192:789–799), matrilysin confers macrophages with their most potent MMP-dependent elastolytic system.

Key Words: cysteine proteinase • elastin • macrophage • matrix metalloproteinase • plasminogen


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