期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 276, 期 28, 页码 26276-26284出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M102356200
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资金
- NCI NIH HHS [CA-16520] Funding Source: Medline
- NHLBI NIH HHS [HL-52132, HL-36110, HL-63284, HL-40387] Funding Source: Medline
- NIAID NIH HHS [AI-23483] Funding Source: Medline
- NIDDK NIH HHS [DK-19525] Funding Source: Medline
Human pulmonary mast cells (MCs) express tryptases alpha and betaI, and both granule serine proteases are exocytosed during inflammatory events. Recombinant forms of these tryptases were generated for the first time to evaluate their substrate specificities at the biochemical level and then to address their physiologic roles in pulmonary inflammation. Analysis of a tryptase-specific, phage display peptide library revealed that tryptase betaI prefers to cleave peptides with 1 or more Pro residues flanked by 2 positively charged residues. Although recombinant tryptase betaI was unable to activate cultured cells that express different types of protease-activated receptors, the numbers of neutrophils increased > 100-fold when enzymatically active tryptase betaI was instilled into the lungs of mice, In contrast, the numbers of lymphocytes and eosinophils in the airspaces did not change significantly. More important, the tryptase betaI-treated mice exhibited normal airway responsiveness. Neutrophils did not extravasate into the lungs of tryptase alpha -treated mice, Thus, this is the first study to demonstrate that the two nearly identical human MC tryptases are functionally distinct in vivo. When MC-deficient W/W-nu mice were given enzymatically active tryptase betaI or its inactive zymogen before pulmonary infection with Klebsiella prteumoniae, tryptase betaI-treated W/W-nu mice had fewer viable bacteria in their lungs relative to zymogen-treated W/W-nu mice, Because neutrophils are required to combat bacterial infections, human tryptase betaI plays a critical role in the antibacterial host defenses of the lung by recruiting neutrophils in a manner that does not alter airway reactivity,
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