Sh. Cho et al., Production of plasminogen activator inhibitor-1 by human mast cells and its possible role in asthma, J IMMUNOL, 165(6), 2000, pp. 3154-3161
The plasminogen activator inhibitor type 1 (PAI-1) has an essential role in
tissue remodeling. The PAI-1 gene was induced by a combination of phorbol
ester and calcium ionophore at the highest level among the inducible human
mast cell genes that we have analyzed on a DNA microarray. PAI-1 was secret
ed by both a human mast cell line (HMC)-1 and primary cultured human mast c
ells upon stimulation, whereas PAI-1 was undetectable in either group of un
stimulated cells. The secretion of PAI-1 was due to de novo synthesis of PA
I-1 rather than secretion of preformed PAI-1, The functional significance o
f PAI-1 secretion was demonstrated by complete inhibition of tissue-type pl
asminogen activator activity with supernatants of stimulated HMC-1 cells. F
urthermore, we were able to regulate PAI-I gene expression in HMC-1 cells b
y known therapeutic agents, High-dose (1 muM) dexamethasone induced PAI-1 m
RNA expression, Cyclosporin down-regulated the expression of the PAI-1 gene
, Cycloheximide abrogated PAI-I mRNA expression, suggesting that transcript
ion of the PAI-1 gene requires de novo synthesis of early gene products, in
cluding transcription factors, Finally, we demonstrated PAI-I in lung mast
cells from a patient with asthmatic attack by double-immunofluorescence stu
dy. This is the first report demonstrating that activated human mast cells
release a striking amount of functionally active PAI-1, These results sugge
st that PAI-1 could play an important role in airway remodeling of asthma,
and inhibition of PAI-1 activity could represent a novel therapeutic approa
ch in the management of airway remodeling.