Tryptase activates TGFbeta in human airway smooth muscle cells via direct proteolysis.
Transforming growth factor beta (TGFbeta) is a key remodelling factor in asthma. It is produced as a latent complex and the main limiting step in TGFbeta bioavailability is its activation. Mast cell tryptase has been shown to stimulate the release of functionally active TGFbeta from human airway smooth muscle (ASM) cells [P. Berger, P.O. Girodet, H. Begueret, O. Ousova, D.W. Perng, R. Marthan, A.F. Walls, J.M. Tunon de Lara, Tryptase-stimulated human airway smooth muscle cells induce cytokine synthesis and mast cell chemotaxis, FASEB J. 17 (2003) 2139-2141]. The aim of this study was to determine if tryptase could cause TGFbeta activation as well as expression in ASM cells via its receptor, proteinase-activated receptor 2 (PAR2). Tryptase caused TGFbeta activation without affecting levels of total TGFbeta. This effect was inhibited by the selective tryptase inhibitor FUT175 and leupeptin but not mimicked by the PAR2 activating peptide SLIGKV-NH(2). Furthermore, the ASM cells used in the study did not express PAR2. The results indicate that tryptase activates TGFbeta via a PAR2-independent proteolytic mechanism in human ASM cells and may help understanding the role of tryptase in asthma.
Tatler
Amanda L
AL
Centre for Respiratory Research, Clinical Sciences Building, City Hospital, University of Nottingham, Hucknall Road, Nottingham NG5 1PB, UK. msxalt@nottingham.ac.uk
Porte
Joanne
J
Knox
Alan
A
Jenkins
Gisli
G
Pang
Linhua
L
D001550:Benzamidines; D001980:Bronchi / Q000166:cytology / Q000201:enzymology*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D009842:Oligopeptides / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000494:pharmacology; D053802:Tryptases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001550:Benzamidines; D006146:Guanidines; D007976:Leupeptins; D009842:Oligopeptides; D044464:Receptor, PAR-2; D016212:Transforming Growth Factor beta; D014361:Trypsin Inhibitors; C515807:seryl-leucyl-isoleucyl-glycyl-lysyl-valinamide; D053802:Tryptases; C032854:leupeptin; C032855:nafamostat