Biochemical and functional characterization of human transmembrane tryptase (TMT)/tryptase γ: TMT is an exocytosed mast cell protease that induces airway hyperresponsiveness in vivo via an interleukin-13/interleukin-4 receptor α/signal transducer and activator of transcription (STAT) 6-dependent pathway

Transmembrane tryptase (TMT)/tryptase γ is a membrane-bound serine protease stored in the secretory granules of human and mouse lung mast cells (MCs). We now show that TMT reaches the external face of the plasma membrane when MCs are induced to degranulate. Analysis of purified recombinant TMT revealed that it is a two-chain neutral protease. Thus, TMT is the only MC protease identified so far which retains its 18-residue propeptide when proteolytically activated. The genes that encode TMT and tryptase βI reside on human chromosome 16p13.3. However, substrate specificity studies revealed that TMT and tryptase βI are functionally distinct even though they are -50% identical. Although TMT is rapidly inactivated by the human plasma serpin α₁-antitrypsin in vitro, administration of recombinant TMT (but not recombinant tryptase βI) into the trachea of mice leads to airway hyperresponsiveness (AHR) and increased expression of interleukin (IL) 13. T cells also increase their expression of IL-13 mRNA when exposed to TMT in vitro. TMT is therefore a novel exocytosed surface mediator that can stimulate those cell types that are in close proximity. TMT induces AHR in normal mice but not in transgenic mice that lack signal transducer and activator of transcription (STAT) 6 or the a-chain of the cytokine receptor that recognizes both IL-4 and IL-13. Based on these data, we conclude that TMT is an exocytosed MC neutral protease that induces AHR in lungs primarily by activating an IL-13/IL-4Rα/STAT6-dependent pathway.