The cytokine-protease connection: identification of a 96-kD THP-1 gelatinase and regulation by interleukin-1 and cytokine inducers.
The induction of proteolytic enzymes is an important mechanism in the migration of monocytes into tissues and body fluids. The monocytic cell line THP-1 was used as a model system to study the production of a particular gelatinase. Upon stimulation with phorbol myristate acetate (PMA) the cells differentiated to the adherent phenotype and produced significant amounts of a 96-kD gelatinase in a dose-dependent way. The secretion rate was maximal between 12 and 24 h after induction. Study of gelatinase mRNA steady state levels showed that the synthesis of THP-1 gelatinase is regulated by PMA at transcriptional or posttranscriptional levels. Stimulation of signal transduction pathways with other substances, including calcium ionophore A 23187, dibutyryl cyclic AMP, and dexamethasone, were ineffective in inducing gelatinase mRNA or enzyme activity. However, THP-1 cells were responsive to the cytokine interleukin (IL)-1 beta, to bacterial lipopolysaccharide (LPS), and the lectin concanavalin A (Con A), the kinetics of gelatinase induction being similar to those of induction by PMA. The THP-1 cells did not synthesize and/or secrete detectable levels of IL-6 after stimulation with PMA, Con A, LPS, or IL-1 beta. The 96-kD monocytic THP-1 gelatinase was shown to be a neutral metalloproteinase that cross-reacted with hepatoma-derived and neutrophil gelatinases in immunoprecipitation experiments. The active enzyme produced by THP-1 cells consistently showed, however, a molecular mass different from that of normal granulocyte-, monocyte-, and tumor cell-derived gelatinases.(ABSTRACT TRUNCATED AT 250 WORDS)
Van Ranst
M
M
Rega Institute for Medical Research, University of Leuven, Belgium.
Norga
K
K
Masure
S
S
Proost
P
P
Vandekerckhove
F
F
Auwerx
J
J
Van Damme
J
J
Opdenakker
G
G
D000595:Amino Acid Sequence; D006528:Carcinoma, Hepatocellular; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003208:Concanavalin A / Q000494:pharmacology*; D018093:Gelatinases; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D007948:Leukemia, Monocytic, Acute; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008113:Liver Neoplasms; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010434:Pepsin A / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D003208:Concanavalin A; D010434:Pepsin A; D018093:Gelatinases; D013755:Tetradecanoylphorbol Acetate