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Mast cell chymase regulation of homeostatic intestinal epithelial barrier function via PAR‐2/MMP‐2‐dependent and ‐independent mechanisms
Author(s) -
Hogan Simon Patrick,
Osterfeld Heather,
Ahrens Richard,
Groschwitz Katherine
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.242.7
Subject(s) - chymase , barrier function , mast cell , chemistry , microbiology and biotechnology , immunology , biology
Homeostatic intestinal barrier function in vivo is regulated through the secretion of the mast cell‐specific serine protease chymase. In the present study, we employ in vitro model systems to delineate the molecular basis of chymase‐mediated regulation of intestinal epithelial barrier function. Chymase stimulation of intestinal epithelial cell monolayers induced a biphasic modification of barrier function. The early phase response occurred within 30 minutes and was dependent on the proteolytic activity of chymase and associated with degradation of the epithelial tight junction protein claudin‐5. The late phase response occurred 12–24 hours following chymase exposure, and was characterized by chymase‐induced protease‐activated receptor‐2 (PAR‐2) activation and matrix metalloproteinase (MMP)‐2 expression and activation. In vitro analysis shows chymase induced PAR‐2 activation and increased MAPK activity and MMP‐2 expression. PAR‐2 and MMP‐2 antagonism significantly attenuated the late‐phase response of chymase‐stimulated barrier dysfunction. Collectively, these results suggest a complex mast cell/chymase‐mediated biphasic regulation of intestinal epithelial barrier function. This work wassupported in part by Food Allergy Anaphylaxis Network and NIH R01AI073553‐01 (S.P.H).