Modulation of thrombin and thrombin receptor peptide mitogenicity by human lung mast cell tryptase.
In previous studies, mast cell tryptase acted as a potent mitogen for fibroblasts from human lung and rodent embryonic tissue but failed to stimulate growth of cultured rat aortic vascular smooth muscle cells (VSMC). The current study shows that tryptase inhibits DNA synthesis in VSMC stimulated by thrombin. However, it does not affect the stimulation of DNA synthesis by the synthetic thrombin receptor peptide Ser-Phe-Phe-Leu-Arg-Asn-Pro (SFFLRNP), which mimics the amino-terminus of thrombin receptor proteolytically activated by thrombin. Nor does tryptase alter the mitogenic response of VSMC to purified growth factors, such as platelet-derived growth factor (PDGF). These data suggest that tryptase inhibits thrombin-induced DNA synthesis without interfering with intracellular mitogenic signaling pathways activated by thrombin or other growth factors. This study further suggests that tryptase neither cleaves nor inactivates thrombin. Therefore, inhibition of thrombin's mitogenic effects by tryptase is not mediated by destruction of thrombin itself. The inhibition by tryptase of thrombin-induced DNA synthesis in VSMC contrasts with the stimulatory effect of tryptase on fibroblasts, in which synergy is observed with thrombin, with thrombin receptor peptide and with other growth factors. These data provide in vitro evidence that mast cell tryptase interferes with thrombin-stimulated vascular smooth muscle growth and suggest that tryptase is a multifunctional growth factor whose actions are cell specific.
Hartmann
T
T
Cardiovascular Research Institute, University of California, San Francisco 94143-0911.
Ruoss
S J
SJ
Caughey
G H
GH
D000818:Animals; D002478:Cells, Cultured; D053818:Chymases; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007531:Isoflurophate / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000201:enzymology*; D008407:Mast Cells / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology*; D015394:Molecular Structure; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D018179:Receptors, Thrombin / Q000737:chemistry*; D012697:Serine Endopeptidases / Q000378:metabolism*; D013917:Thrombin / Q000737:chemistry / Q000494:pharmacology*; D053802:Tryptases
D008934:Mitogens; D009842:Oligopeptides; D010446:Peptide Fragments; D018179:Receptors, Thrombin; D007531:Isoflurophate; C088987:seryl-phenylalanyl-phenylalanyl-leucyl-arginyl-asparaginyl-proline; D004247:DNA; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D013917:Thrombin; C509223:Tpsab1 protein, rat; C509221:Tpsb2 protein, rat; D053802:Tryptases