Identification of TIMP-2 in human alveolar macrophages. Regulation of biosynthesis is opposite to that of metalloproteinases and TIMP-1.
We have identified the metalloproteinase inhibitor TIMP-2 as a secreted product of human alveolar macrophages. In contrast to human fibroblasts, TIMP-2 was released from macrophages free of any apparent complexed metalloproteinases. Also in marked distinction to fibroblasts, TIMP-2 secretion from mononuclear phagocytes was subject to modulation by a variety of agents. TIMP-2 was synthesized by macrophages placed in culture under basal conditions in amounts approximately 30% of those secreted by fibroblasts on a per cell basis. The additions of lipopolysaccharide, denatured type I collagen, and zymosan to culture medium each resulted in a dose-dependent and profound decrease in macrophage TIMP-2 protein production and steady-state mRNA levels. In contrast, all of these agents markedly enhanced the biosynthesis of macrophage interstitial collagenase and TIMP-1 as assessed by analysis of identical cell and conditioned media samples. In human fibroblasts, TIMP-2 biosynthesis was unaffected by interleukin-1, tumor necrosis factor-alpha, platelet-derived growth factor, and phorbol ester despite the massive collagenase stimulation induced by each of these agents. We conclude that TIMP-2 is a potentially important mononuclear phagocyte product whose biosynthesis is regulated in a distinct and completely opposite manner to that of collagenase and TIMP-1.
Shapiro
S D
SD
Department of Medicine, Jewish Hospital, Washington University Medical Center, St. Louis, Missouri 63110.
Kobayashi
D K
DK
Welgus
H G
HG
D000328:Adult; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005780:Gelatin / Q000494:pharmacology; D006023:Glycoproteins / Q000096:biosynthesis* / Q000302:isolation & purification; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000302:isolation & purification; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D012879:Skin Physiological Phenomena; D012907:Smoking / Q000503:physiopathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D006023:Glycoproteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009363:Neoplasm Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D005780:Gelatin; D008666:Metalloendopeptidases; D013755:Tetradecanoylphorbol Acetate