Activation of paracrine TGF-beta1 signaling upon stimulation and degranulation of rat serosal mast cells: a novel function for chymase.
As a source of transforming growth factor beta1 (TGF-beta1), mast cells have been implicated as potential effector cells in many pathological processes. However, the mechanisms by which mast cells express, secrete, and activate TGF-beta1 have remained vague. We show here by means of RT-PCR, immunoblotting, and immunocytochemistry that isolated rat peritoneal mast cells synthesize and store large latent TGF-beta1 in their chymase 1-containing secretory granules. Mast cell stimulation and degranulation results in rapid secretion of the latent TGF-beta1, which is converted by chymase 1 into an active form recognized by the type II TGF-beta serine/threonine kinase receptor (TbetaRII). Thus, mast cells secrete active TGF-beta1 by a unique secretory mechanism in which latent TGF-beta1 and the activating enzyme chymase 1 are coreleased. The activation of latent TGF-beta1 specifically by chymase was verified using recombinant human latent TGF-beta1 and recombinant human chymase. In isolated TbetaRI- and TbetaRII-expressing peritoneal macrophages, the activated TGF-beta1 induces the expression of the plasminogen activator inhibitor 1 (PAI-1), whereas in the mast cells, the levels of TbetaRI, TbetaRII, and PAI-1 expression were below detection. Selective stimulation of mast cells in vivo in the rat peritoneal cavity leads to rapid overexpression of TGF-beta1 in peritoneal mast cells and of TbetaRs in peritoneal macrophages. These data strongly suggest that mast cells can act as potent paracrine effector cells both by secreting active TGF-beta1 and by enhancing its response in target cells.
Lindstedt
K A
KA
Wihuri Research Institute, FIN-00140 Helsinki, Finland. ken.lindstedt@wri.fi
Wang
Y
Y
Shiota
N
N
Saarinen
J
J
Hyytiäinen
M
M
Kokkonen
J O
JO
Keski-Oja
J
J
Kovanen
P T
PT
D000818:Animals; D015550:Cell Degranulation; D053818:Chymases; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D019899:Paracrine Communication; D010529:Peritoneal Cavity / Q000166:cytology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010994:Pleura / Q000166:cytology; D011499:Protein Processing, Post-Translational; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D012704:Serous Membrane / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012697:Serine Endopeptidases; C509226:CMA1 protein, human; D053818:Chymases; C509228:Cma1 protein, rat