Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells.
Airway remodeling with smooth muscle cell (SMC) hyperplasia is a feature of chronic asthma. We investigated the potential for tryptase, the major secretory product of human mast cells, to act as a growth factor for human airway SMCs. Because this serine protease can activate proteinase-activated receptor-2 (PAR-2), we also examined the actions of SLIGKV, a peptide agonist of PAR-2. Incubation with lung tryptase provoked a twofold increase in [(3)H]thymidine incorporation; a similar increase in cell numbers was found when we used the MTS assay. The effect was catalytic site dependent, being abolished by the protease inhibitors leupeptin and benzamidine and by heat inactivation of the enzyme. Tryptase-induced DNA synthesis was inhibited by preincubation of the cells with pertussis toxin, calphostin C, or genistein. Transduction mechanisms are thus likely to involve a pertussis toxin-sensitive G protein, protein kinase C, and tyrosine kinase. SLIGKV elicited a response on SMCs similar to that of tryptase. Tryptase could provide an important stimulus for SMC proliferation in asthmatic airways, by acting on PAR-2.
Berger
P
P
Immunopharmacology Group, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
Perng
D W
DW
Thabrew
H
H
Compton
S J
SJ
Cairns
J A
JA
McEuen
A R
AR
Marthan
R
R
Tunon De Lara
J M
JM
Walls
A F
AF
D001249:Asthma / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000166:cytology*; D008407:Mast Cells / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology*; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000819:agonists*; D012697:Serine Endopeptidases / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053802:Tryptases
D009842:Oligopeptides; D011480:Protease Inhibitors; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C109968:seryl-leucyl-isoleucyl--glycyl-lysyl-valine; D004247:DNA; D012697:Serine Endopeptidases; D053802:Tryptases