Differential regulation of matrix metalloproteinase-9 by monocytes adherent to collagen and platelets.
Circulating monocytes adhere to platelets and matrix proteins at sites of vascular injury, where engagement of specific surface tethering molecules mediates outside-in signaling and synthesis of gene products by the leukocytes. Here we demonstrate that interaction of isolated human monocytes with collagen induces matrix metalloproteinase-9 (MMP-9; gelatinase B) synthesis by monocytes, a process that is greatly enhanced in the presence of platelets. MMP-9 is a potent matrix degrading enzyme implicated in atherosclerotic plaque rupture, aneurysm formation, and other vascular syndromes. Synthesis of MMP-9 by monocytes is tightly regulated and synergistically increased following adhesion to collagen and platelets. Adhesion to control matrix proteins alone did not result in MMP-9 protein production and, similarly, adhesion of monocytes to platelets activated with thrombin in suspension was not sufficient to induce MMP-9 synthesis in the absence of monocyte adhesion to collagen. Interruption of intercellular contact between platelets and monocytes dramatically inhibited MMP-9 synthesis. These observations demonstrate that discrete adhesion-dependent signaling pathways govern MMP-9 synthesis by monocytes. The synthesis of MMP-9 by monocytes may be critical in vascular syndromes and other pathological processes that are dependent on dysregulated cell-cell and cell-matrix interactions.
Galt
S W
SW
Division of Vascular Surgery, Department of Internal Medicine, Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, USA. sgalt@hsc.utah.edu
Lindemann
S
S
Medd
D
D
Allen
L L
LL
Kraiss
L W
LW
Harris
E S
ES
Prescott
S M
SM
McIntyre
T M
TM
Weyrich
A S
AS
Zimmerman
G A
GA
D001792:Blood Platelets / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007797:Laminin / Q000378:metabolism / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D018932:Chemokine CCL2; D007797:Laminin; D012333:RNA, Messenger; D003094:Collagen; D020780:Matrix Metalloproteinase 9