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PAR2 Activation Protects Against Colitis but Inhibits Epithelial Wound Healing
Author(s) -
Trusevych Elizabeth,
Iablokov Vadim,
Dicay Michael,
Beck Paul,
MacNaughton Wallace
Publication year - 2015
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.29.1_supplement.142.3
Subject(s) - in vivo , wound healing , inflammation , receptor , cyclooxygenase , chemistry , in vitro , cell , caco 2 , cancer research , medicine , immunology , biology , enzyme , biochemistry , microbiology and biotechnology
Aims Protease‐activated receptor (PAR)2 activation increases the expression of cyclooxygenase (COX)‐2 in intestinal epithelial cells. We tested the hypothesis that PAR2‐induced COX‐2 regulates intestinal inflammation and modulates epithelial wound healing. Methods PAR2 was activated using the selective activating peptide 2f‐LIGRLO. Circular wounds in Caco2 cell monolayers were monitored with live‐cell imaging. In vivo, epithelial damage was induced by giving WT and PAR2 KO (C57Bl/6) mice 2.5% DSS for 5‐7 days. Results Activation of PAR2 in Caco2 cells significantly increased COX‐2 protein (4.2‐fold) and PGE 2 metabolites (9.6‐fold). In vivo , preliminary results showed less COX‐2 protein in PAR2 KO mice given DSS compared to WT mice. The PAR2 KO mice also lost significantly more weight and had higher histological damage scores compared to WT mice. We next determined the effect of PAR2‐induced COX‐2 on epithelial wound healing in vitro . Surprisingly, PAR2 activation significantly inhibited the rate of wound closure over 48 hr (79.3±2.5% wound closure) compared to control (94.3±0.5%), independently of COX‐2 activity. PAR2 activation had no effect on proliferation, but significantly inhibited cell migration. Conclusions PAR2 activation was shown to be protective in vivo , which correlated with the expression of COX‐2. We also uncovered a novel COX‐2‐independent effect of PAR2, reducing the rate of wound healing by inhibiting cell migration. Our results show that PAR2 plays differential roles in regulating epithelial response to injury and inflammation. Support: Crohn's and Colitis Canada, Alberta IBD Consortium, Alberta Cancer Foundation.