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Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediate Clostridium difficile toxin A enteritis

Cottrell, Graeme S ; Amadesi, Silvia ; Pikios, Stella ; Camerer, Eric ; Willardsen, J Adam ; Murphy, Brett R ; Caughey, George H ; Wolters, Paul J ; Coughlin, Shaun R and Peterson, Anders , et al. (2007) In Gastroenterology 132(7). p.2422-2437
Abstract

BACKGROUND & AIMS: We studied the role of protease-activated receptor 2 (PAR(2)) and its activating enzymes, trypsins and tryptase, in Clostridium difficile toxin A (TxA)-induced enteritis.

METHODS: We injected TxA into ileal loops in PAR(2) or dipeptidyl peptidase I (DPPI) knockout mice or in wild-type mice pretreated with tryptase inhibitors (FUT-175 or MPI-0442352) or soybean trypsin inhibitor. We examined the effect of TxA on expression and activity of PAR(2) and trypsin IV messenger RNA in the ileum and cultured colonocytes. We injected activating peptide (AP), trypsins, tryptase, and p23 in wild-type mice, some pretreated with the neurokinin 1 receptor antagonist SR140333.

RESULTS: TxA increased fluid secretion,... (More)

BACKGROUND & AIMS: We studied the role of protease-activated receptor 2 (PAR(2)) and its activating enzymes, trypsins and tryptase, in Clostridium difficile toxin A (TxA)-induced enteritis.

METHODS: We injected TxA into ileal loops in PAR(2) or dipeptidyl peptidase I (DPPI) knockout mice or in wild-type mice pretreated with tryptase inhibitors (FUT-175 or MPI-0442352) or soybean trypsin inhibitor. We examined the effect of TxA on expression and activity of PAR(2) and trypsin IV messenger RNA in the ileum and cultured colonocytes. We injected activating peptide (AP), trypsins, tryptase, and p23 in wild-type mice, some pretreated with the neurokinin 1 receptor antagonist SR140333.

RESULTS: TxA increased fluid secretion, myeloperoxidase activity in fluid and tissue, and histologic damage. PAR(2) deletion decreased TxA-induced ileitis, reduced luminal fluid secretion by 20%, decreased tissue and fluid myeloperoxidase by 50%, and diminished epithelial damage, edema, and neutrophil infiltration. DPPI deletion reduced secretion by 20% and fluid myeloperoxidase by 55%. In wild-type mice, FUT-175 or MPI-0442352 inhibited secretion by 24%-28% and tissue and fluid myeloperoxidase by 31%-71%. Soybean trypsin inhibitor reduced secretion to background levels and tissue myeloperoxidase by up to 50%. TxA increased expression of PAR(2) and trypsin IV in enterocytes and colonocytes and caused a 2-fold increase in Ca(2+) responses to PAR(2) AP. AP, tryptase, and trypsin isozymes (trypsin I/II, trypsin IV, p23) caused ileitis. SR140333 prevented AP-induced ileitis.

CONCLUSIONS: PAR(2) and its activators are proinflammatory in TxA-induced enteritis. TxA stimulates existing PAR(2) and up-regulates PAR(2) and activating proteases, and PAR(2) causes inflammation by neurogenic mechanisms.

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type
Contribution to journal
publication status
published
keywords
Animals, Bacterial Toxins/pharmacology, Cathepsin C/deficiency, Cells, Cultured, Colon/cytology, Enteritis/chemically induced, Enterotoxins/pharmacology, Granulocytes/pathology, Ileitis/etiology, Ileum/metabolism, Intestinal Mucosa/metabolism, Intestines/pathology, Mice, Mice, Knockout, Nervous System/metabolism, Peptide Hydrolases/metabolism, Peroxidase/metabolism, Receptor, PAR-2/deficiency, Receptors, Neurokinin-1/metabolism, Trypsin/metabolism, Trypsin Inhibitors/pharmacology, Tryptases/pharmacology, Up-Regulation
in
Gastroenterology
volume
132
issue
7
pages
2422 - 2437
publisher
Elsevier
external identifiers
  • scopus:34249991980
  • pmid:17570216
ISSN
0016-5085
DOI
10.1053/j.gastro.2007.03.101
language
English
LU publication?
no
id
ec362015-81ab-4dd2-8526-1901f6499cd8
date added to LUP
2020-07-22 14:11:41
date last changed
2024-01-02 14:47:58
@article{ec362015-81ab-4dd2-8526-1901f6499cd8,
  abstract     = {{<p>BACKGROUND &amp; AIMS: We studied the role of protease-activated receptor 2 (PAR(2)) and its activating enzymes, trypsins and tryptase, in Clostridium difficile toxin A (TxA)-induced enteritis.</p><p>METHODS: We injected TxA into ileal loops in PAR(2) or dipeptidyl peptidase I (DPPI) knockout mice or in wild-type mice pretreated with tryptase inhibitors (FUT-175 or MPI-0442352) or soybean trypsin inhibitor. We examined the effect of TxA on expression and activity of PAR(2) and trypsin IV messenger RNA in the ileum and cultured colonocytes. We injected activating peptide (AP), trypsins, tryptase, and p23 in wild-type mice, some pretreated with the neurokinin 1 receptor antagonist SR140333.</p><p>RESULTS: TxA increased fluid secretion, myeloperoxidase activity in fluid and tissue, and histologic damage. PAR(2) deletion decreased TxA-induced ileitis, reduced luminal fluid secretion by 20%, decreased tissue and fluid myeloperoxidase by 50%, and diminished epithelial damage, edema, and neutrophil infiltration. DPPI deletion reduced secretion by 20% and fluid myeloperoxidase by 55%. In wild-type mice, FUT-175 or MPI-0442352 inhibited secretion by 24%-28% and tissue and fluid myeloperoxidase by 31%-71%. Soybean trypsin inhibitor reduced secretion to background levels and tissue myeloperoxidase by up to 50%. TxA increased expression of PAR(2) and trypsin IV in enterocytes and colonocytes and caused a 2-fold increase in Ca(2+) responses to PAR(2) AP. AP, tryptase, and trypsin isozymes (trypsin I/II, trypsin IV, p23) caused ileitis. SR140333 prevented AP-induced ileitis.</p><p>CONCLUSIONS: PAR(2) and its activators are proinflammatory in TxA-induced enteritis. TxA stimulates existing PAR(2) and up-regulates PAR(2) and activating proteases, and PAR(2) causes inflammation by neurogenic mechanisms.</p>}},
  author       = {{Cottrell, Graeme S and Amadesi, Silvia and Pikios, Stella and Camerer, Eric and Willardsen, J Adam and Murphy, Brett R and Caughey, George H and Wolters, Paul J and Coughlin, Shaun R and Peterson, Anders and Knecht, Wolfgang and Pothoulakis, Charalabos and Bunnett, Nigel W and Grady, Eileen F}},
  issn         = {{0016-5085}},
  keywords     = {{Animals; Bacterial Toxins/pharmacology; Cathepsin C/deficiency; Cells, Cultured; Colon/cytology; Enteritis/chemically induced; Enterotoxins/pharmacology; Granulocytes/pathology; Ileitis/etiology; Ileum/metabolism; Intestinal Mucosa/metabolism; Intestines/pathology; Mice; Mice, Knockout; Nervous System/metabolism; Peptide Hydrolases/metabolism; Peroxidase/metabolism; Receptor, PAR-2/deficiency; Receptors, Neurokinin-1/metabolism; Trypsin/metabolism; Trypsin Inhibitors/pharmacology; Tryptases/pharmacology; Up-Regulation}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{2422--2437}},
  publisher    = {{Elsevier}},
  series       = {{Gastroenterology}},
  title        = {{Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediate Clostridium difficile toxin A enteritis}},
  url          = {{http://dx.doi.org/10.1053/j.gastro.2007.03.101}},
  doi          = {{10.1053/j.gastro.2007.03.101}},
  volume       = {{132}},
  year         = {{2007}},
}