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Mast cell tryptase controls paracellular permeability of the intestine: role of protease-activated receptor 2 and beta-arrestins

Jacob, C., Yang, P.-C., Darmoul, D., Amadesi, S., Saito, T., Cottrell, G. S. ORCID:, Coelho, A.-M., Singh, P., Grady, E. F., Perdue, M. and Bunnett, N. W. (2005) Mast cell tryptase controls paracellular permeability of the intestine: role of protease-activated receptor 2 and beta-arrestins. Journal of Biological Chemistry, 280 (31). pp. 936-948. ISSN 1083-351X

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To link to this item DOI: 10.1074/jbc.M506338200


Tight junctions between intestinal epithelial cells prevent ingress of luminal macromolecules and bacteria and protect against inflammation and infection. During stress and inflammation, mast cells mediate increased mucosal permeability by unknown mechanisms. We hypothesized that mast cell tryptase cleaves protease-activated receptor 2 (PAR2) on colonocytes to increase paracellular permeability. Colonocytes expressed PAR2 mRNA and responded to PAR2 agonists with increased [Ca2+]i. Supernatant from degranulated mast cells increased [Ca2+]i in colonocytes, which was prevented by a tryptase inhibitor, and desensitized responses to PAR2 agonist, suggesting PAR2 cleavage. When applied to the basolateral surface of colonocytes, PAR2 agonists and mast cell supernatant decreased transepithelial resistance, increased transepithelial flux of macromolecules, and induced redistribution of tight junction ZO-1 and occludin and perijunctional F-actin. When mast cells were co-cultured with colonocytes, mast cell degranulation increased paracellular permeability of colonocytes. This was prevented by a tryptase inhibitor. We determined the role of ERK1/2 and of beta-arrestins, which recruit ERK1/2 to PAR2 in endosomes and retain ERK1/2 in the cytosol, on PAR2-mediated alterations in permeability. An ERK1/2 inhibitor abolished the effects of PAR2 agonist on permeability and redistribution of F-actin. Down-regulation of beta-arrestins with small interfering RNA inhibited PAR2-induced activation of ERK1/2 and suppressed PAR2-induced changes in permeability. Thus, mast cells signal to colonocytes in a paracrine manner by release of tryptase and activation of PAR2. PAR2 couples to beta-arrestin-dependent activation of ERK1/2, which regulates reorganization of perijunctional F-actin to increase epithelial permeability. These mechanisms may explain the increased epithelial permeability of the intestine during stress and inflammation.

Item Type:Article
Divisions:Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
No Reading authors. Back catalogue items
ID Code:30277
Uncontrolled Keywords:Actins/metabolism Arrestins/*physiology Calcium/metabolism Cell Line Coculture Techniques Colon/*cytology/enzymology/*physiology Humans Mast Cells/enzymology Mitogen-Activated Protein Kinase 1/physiology Mitogen-Activated Protein Kinase 3/physiology Permeability RNA, Small Interfering Receptor, PAR-2/agonists/genetics/*physiology Serine Endopeptidases/*physiology Signal Transduction/physiology Tight Junctions/enzymology/*physiology Tryptases
Publisher:American Society for Biochemistry and Molecular Biology

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