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* Wihuri Research Institute, FIN-00140 Helsinki, Finland;
Protein Chemistry Laboratory, Institute of Biotechnology, FIN-00014 University of Helsinki, Finland; and
Departments of Pathology and Virology, Haartman Institute, FIN-00014 University of Helsinki, Finland
1Correspondence: Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland. E-mail: ken.lindstedt{at}wri.fi
As a source of transforming growth factor ß1 (TGF-ß1), 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-ß1 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-ß1 in their chymase 1-containing secretory granules. Mast cell stimulation and degranulation results in rapid secretion of the latent TGF-ß1, which is converted by chymase 1 into an active form recognized by the type II TGF-ß serine/threonine kinase receptor (TßRII). Thus, mast cells secrete active TGF-ß1 by a unique secretory mechanism in which latent TGF-ß1 and the activating enzyme chymase 1 are coreleased. The activation of latent TGF-ß1 specifically by chymase was verified using recombinant human latent TGF-ß1 and recombinant human chymase. In isolated TßRI- and TßRII-expressing peritoneal macrophages, the activated TGF-ß1 induces the expression of the plasminogen activator inhibitor 1 (PAI-1), whereas in the mast cells, the levels of TßRI, TßRII, 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-ß1 in peritoneal mast cells and of TßRs in peritoneal macrophages. These data strongly suggest that mast cells can act as potent paracrine effector cells both by secreting active TGF-ß1 and by enhancing its response in target cells.—Lindstedt, K. A., Wang, Y., Shiota, N., Saarinen, J., Hyytiäinen, M., Kokkonen, J. O., Keski-Oja, J., Kovanen, P. T. Activation of paracrine TGF-ß1 signaling upon stimulation and degranulation of rat serosal mast cells: a novel function for chymase.
Key Words: recombinant chymase • proteolysis • TGF-ß activation • TGF-ß receptors • gene regulation
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