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Originally published In Press as doi:10.1074/jbc.M506338200 on July 18, 2005

J. Biol. Chem., Vol. 280, Issue 36, 31936-31948, September 9, 2005
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Mast Cell Tryptase Controls Paracellular Permeability of the Intestine

ROLE OF PROTEASE-ACTIVATED RECEPTOR 2 AND {beta}-ARRESTINS*

Claire Jacob{ddagger}§, Ping-Chang Yang§, Dalila Darmoul{ddagger}§, Silvia Amadesi{ddagger}§, Toshiyuki Saito{ddagger}§, Graeme S. Cottrell{ddagger}, Anne-Marie Coelho{ddagger}, Pamela Singh¶, Eileen F. Grady{ddagger}, Mary Perdue¶, and Nigel W. Bunnett{ddagger}||

From the {ddagger}Departments of Surgery and Physiology, University of California, San Francisco, California 94143 and the Intestinal Disease Research Program, McMaster University, Hamilton, Ontario L8S 4L8, Canada

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.

Received for publication, June 10, 2005

* This work was supported by National Institutes of Health Grants DK43207, DK57840, DK39957, and DK52388. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

|| To whom correspondence should be addressed: University of California, San Francisco, 521 Parnassus Ave., San Francisco, CA 94143-0660. Tel.: 415-476-0489; Fax: 415-476-0936; E-mail: nigelb{at}itsa.ucsf.edu.


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