Neutrophil activator of matrix metalloproteinase-2 (NAM).
We have isolated a novel soluble factor(s), neutrophil activator of matrix metalloproteinases (NAM), secreted by unstimulated normal human peripheral blood neutrophils that causes the activation of cell secreted promatrix metalloproteinase-2 (proMMP-2). Partially purified preparations of NAM have been isolated from the conditioned media of neutrophils employing gelatin-Sepharose chromatography and differential membrane filter centrifugation. NAM activity, as assessed by exposing primary human umbilical vein endothelial cells (HUVEC) or HT1080 cells to NAM followed by gelatin zymography, was seen within one hour. Tissue inhibitor of metalloproteinase-2 (TIMP-2) and hydroxamic acid derived inhibitors of MMPs (CT1746 and BB94) abrogated the activation of proMMP-2 by NAM, while inhibitors of serine and cysteine proteases showed no effect. NAM also produced an increase in TIMP-2 binding to HUVEC and HT1080 cell surfaces that was inhibited by TIMP-2, CT1746, and BB94. Time-dependent increases in MT1-MMP protein and mRNA were seen following the addition of NAM to cells. These data support a role for NAM in cancer dissemination.
Rollo
Ellen E
EE
Departments of Research and Medicine, Veterans Affairs Medical Center, Mail Code 151, Northport, NY, 11768, USA.
Hymowitz
Michelle
M
Schmidt
Cathleen E
CE
Montana
Steve
S
Foda
Hussein
H
Zucker
Stanley
S
D000328:Adult; D000577:Amides / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D056649:Cathepsin G; D002403:Cathepsins / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D017077:Culture Media, Conditioned / Q000737:chemistry; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D015759:Ionomycin / Q000494:pharmacology; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009504:Neutrophils / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000302:isolation & purification* / Q000494:pharmacology / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012697:Serine Endopeptidases / Q000494:pharmacology; D013379:Substrate Specificity; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology; D014471:Umbilical Veins
D000577:Amides; C099496:CT 1746; D017077:Culture Media, Conditioned; D004792:Enzyme Precursors; D009842:Oligopeptides; D011480:Protease Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D013876:Thiophenes; C028656:eglin proteinase inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; D000001:Calcimycin; D010649:Phenylalanine; D015759:Ionomycin; C024998:N-formylnorleucyl-leucyl-4-phenylalanine; C002101:chymostatin; C080985:batimastat; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D013755:Tetradecanoylphorbol Acetate