Matrilysin-dependent elastolysis by human macrophages.
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.
Filippov
Sergey
S
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA.
Caras
Ingrid
I
Murray
Richard
R
Matrisian
Lynn M
LM
Chapman
Harold A
HA
Shapiro
Steven
S
Weiss
Stephen J
SJ
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D004549:Elastin / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010196:Pancreatic Elastase / Q000235:genetics / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism
D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D010958:Plasminogen; D004549:Elastin; D002403:Cathepsins; D010960:Plasminogen Activators; D010196:Pancreatic Elastase; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9