Activation of paracrine TGF‐β1 signaling upon stimulation and degranulation of rat serosal mast cells: a novel function for chymase

As a source of transforming growth factor β1 (TGF‐β1), 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‐β1 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‐β1 in their chymase 1‐containing secretory granules. Mast cell stimulation and degranulation results in rapid secretion of the latent TGF‐β1, which is converted by chymase 1 into an active form recognized by the type II TGF‐β serine/ threonine kinase receptor (TβRII). Thus, mast cells secrete active TGF‐β1 by a unique secretory mechanism in which latent TGF‐β1 and the activating enzyme chymase 1 are coreleased. The activation of latent TGF‐β1 specifically by chymase was verified using recombinant human latent TGF‐β1 and recombinant human chymase. In isolated TβRI‐ and TβRII‐expressing peritoneal macrophages, the activated TGF‐β1 induces the expression of the plasminogen activator inhibitor 1 (PAI‐1), whereas in the mast cells, the levels of TβRI, TβRII, 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‐β1 in peritoneal mast cells and of TβRs in peritoneal macrophages. These data strongly suggest that mast cells can act as potent paracrine effector cells both by secreting active TGF‐β1 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‐β1 signaling upon stimulation and degranulation of rat serosal mast cells: a novel function for chymase. FASEB J. 15, 1377–1388 (2001)