| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Neuro-Gastroenterology and Nutrition Unit,* Institut National de la Recherche Agronomique, Toulouse, France; the Department of Pharmacology and Therapeutics and Physiology and Biophysics,¶ Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; the Department of Surgery and Physiology, University of California at San Francisco, San Francisco, California; and the R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania
Proteinase-activated receptor (PAR)-2, a G-protein-coupled receptor for trypsin and mast cell tryptase, is highly expressed in the intestine. Luminal trypsin and tryptase are elevated in the colon of inflammatory bowel disease patients. We hypothesized that luminal proteinases activate PAR-2 and induce colonic inflammation. Mice received intracolonically PAR-2 agonists (trypsin, tryptase, and a selective PAR-2-activating peptide) or control drugs (boiled enzymes, inactive peptide) and inflammatory parameters were followed at various times after this treatment. Colonic administration of PAR-2 agonists up-regulated PAR-2 expression and induced an inflammatory reaction characterized by granulocyte infiltration, increased wall thickness, tissue damage, and elevated T-helper cell type 1 cytokine. The inflammation was maximal between 4 and 6 hours and was resolved 48 hours after the intracolonic administration. PAR-2 activation also increased paracellular permeability of the colon and induced bacterial trans-location into peritoneal organs. These proinflammatory and pathophysiological changes observed in wild-type mice were not detected in PAR-2-deficient mice. Luminal proteinases activate PAR-2 in the mouse colon to induce inflammation and disrupt the integrity of the intestinal barrier. Because trypsin and tryptase are found at high levels in the colon lumen of patients with Crohn’s disease or ulcerative colitis, our data may bear directly on the pathophysiology of human inflammatory bowel diseases.
This article has been cited by other articles:
 |
|
 |
|
  V. A. Swystun, B. Renaux, F. Moreau, S. Wen, M. A. Peplowski, M. D. Hollenberg, and W. K. MacNaughton Serine proteases decrease intestinal epithelial ion permeability by activation of protein kinase C{zeta} Am J Physiol Gastrointest Liver Physiol, July 1, 2009; 297(1): G60 - G70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dabek, L. Ferrier, R. Roka, K. Gecse, A. Annahazi, J. Moreau, J. Escourrou, C. Cartier, G. Chaumaz, M. Leveque, et al. Luminal Cathepsin G and Protease-Activated Receptor 4: A Duet Involved in Alterations of the Colonic Epithelial Barrier in Ulcerative Colitis Am. J. Pathol., July 1, 2009; 175(1): 207 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Sun, W. Li, R. She, D. Wang, D. Han, R. Li, Y. Ding, and Z. Yue Evidence for a role of mast cells in the mucosal injury induced by Newcastle disease virus Poult. Sci., March 1, 2009; 88(3): 554 - 561. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Wilson, R. Harada, L. LeDuy, M. D. Hollenberg, and A. Nepveu CUX1 Transcription Factor Is a Downstream Effector of the Proteinase-activated Receptor 2 (PAR2) J. Biol. Chem., January 2, 2009; 284(1): 36 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Namkung, J. S. Yoon, K. H. Kim, and M. G. Lee PAR2 exerts local protection against acute pancreatitis via modulation of MAP kinase and MAP kinase phosphatase signaling Am J Physiol Gastrointest Liver Physiol, November 1, 2008; 295(5): G886 - G894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Sutton, A. Zhao, K. B. Madden, J. E. Elfrey, B. A. Tuft, C. A. Sullivan, J. F. Urban Jr., and T. Shea-Donohue Anti-Inflammatory Mechanisms of Enteric Heligmosomoides polygyrus Infection against Trinitrobenzene Sulfonic Acid-Induced Colitis in a Murine Model Infect. Immun., October 1, 2008; 76(10): 4772 - 4782. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Hyun, P Andrade-Gordon, M Steinhoff, and N Vergnolle Protease-activated receptor-2 activation: a major actor in intestinal inflammation Gut, September 1, 2008; 57(9): 1222 - 1229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Barbara and C. Cremon Serine proteases: new players in diarrhoea-predominant irritable bowel syndrome Gut, August 1, 2008; 57(8): 1035 - 1037. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Shpacovitch, M. Feld, M. D. Hollenberg, T. A. Luger, and M. Steinhoff Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity J. Leukoc. Biol., June 1, 2008; 83(6): 1309 - 1322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Ferrier Significance of increased human colonic permeability in response to corticotrophin-releasing hormone (CRH) Gut, January 1, 2008; 57(1): 7 - 9. [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Vesey, W. A. Kruger, P. Poronnik, G. C. Gobe, and D. W. Johnson Proinflammatory and proliferative responses of human proximal tubule cells to PAR-2 activation Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1441 - F1449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D Soderholm Stress-related changes in oesophageal permeability: filling the gaps of GORD? Gut, September 1, 2007; 56(9): 1177 - 1180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Moussa, J. Apostolopoulos, P. Davenport, J. Tchongue, and P. G. Tipping Protease-Activated Receptor-2 Augments Experimental Crescentic Glomerulonephritis Am. J. Pathol., September 1, 2007; 171(3): 800 - 808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Roka, A. Ait-Belgnaoui, C. Salvador-Cartier, R. Garcia-Villar, J. Fioramonti, H. Eutamene, and L. Bueno Dexamethasone prevents visceral hyperalgesia but not colonic permeability increase induced by luminal protease-activated receptor-2 agonist in rats Gut, August 1, 2007; 56(8): 1072 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kida, H. Inoue, T. Shimizu, and K. Kuwano Serratia marcescens Serralysin Induces Inflammatory Responses through Protease-Activated Receptor 2 Infect. Immun., January 1, 2007; 75(1): 164 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C A Dinarello and S-H Kim IL-32, a novel cytokine with a possible role in disease Ann Rheum Dis, November 1, 2006; 65(suppl_3): iii61 - iii64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Amadesi, G. S. Cottrell, L. Divino, K. Chapman, E. F. Grady, F. Bautista, R. Karanjia, C. Barajas-Lopez, S. Vanner, N. Vergnolle, et al. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase C{varepsilon}- and A-dependent mechanisms in rats and mice J. Physiol., September 1, 2006; 575(2): 555 - 571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cattaruzza, N. Cenac, E. Barocelli, M. Impicciatore, E. Hyun, N. Vergnolle, and C. Sternini Protective Effect of Proteinase-Activated Receptor 2 Activation on Motility Impairment and Tissue Damage Induced by Intestinal Ischemia/Reperfusion in Rodents Am. J. Pathol., July 1, 2006; 169(1): 177 - 188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Demaude, C Salvador-Cartier, J Fioramonti, L Ferrier, and L Bueno Phenotypic changes in colonocytes following acute stress or activation of mast cells in mice: implications for delayed epithelial barrier dysfunction Gut, May 1, 2006; 55(5): 655 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chignard and D. Pidard Neutrophil and Pathogen Proteinases versus Proteinase-Activated Receptor-2 Lung Epithelial Cells: More Terminators than Activators. Am. J. Respir. Cell Mol. Biol., April 1, 2006; 34(4): 394 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Holzhausen, L. C. Spolidorio, R. P. Ellen, M.-C. Jobin, M. Steinhoff, P. Andrade-Gordon, and N. Vergnolle Protease-Activated Receptor-2 Activation: A Major Role in the Pathogenesis of Porphyromonas gingivalis Infection Am. J. Pathol., April 1, 2006; 168(4): 1189 - 1199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Novick, M. Rubinstein, T. Azam, A. Rabinkov, C. A. Dinarello, and S.-H. Kim Proteinase 3 is an IL-32 binding protein PNAS, February 28, 2006; 103(9): 3316 - 3321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Noorbakhsh, S. Tsutsui, N. Vergnolle, L. A. Boven, N. Shariat, M. Vodjgani, K. G. Warren, P. Andrade-Gordon, M. D. Hollenberg, and C. Power Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis J. Exp. Med., February 21, 2006; 203(2): 425 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Swift, A. J. Leger, J. Talavera, L. Zhang, A. Bohm, and A. Kuliopulos Role of the PAR1 Receptor 8th Helix in Signaling: THE 7-8-1 RECEPTOR ACTIVATION MECHANISM J. Biol. Chem., February 17, 2006; 281(7): 4109 - 4116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jacob, P.-C. Yang, D. Darmoul, S. Amadesi, T. Saito, G. S. Cottrell, A.-M. Coelho, P. Singh, E. F. Grady, M. Perdue, et al. Mast Cell Tryptase Controls Paracellular Permeability of the Intestine: ROLE OF PROTEASE-ACTIVATED RECEPTOR 2 AND {beta}-ARRESTINS J. Biol. Chem., September 9, 2005; 280(36): 31936 - 31948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Hansen, P. M. Sherman, L. Cellars, P. Andrade-Gordon, Z. Pan, A. Baruch, J. L. Wallace, M. D. Hollenberg, and N. Vergnolle A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis PNAS, June 7, 2005; 102(23): 8363 - 8368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N Vergnolle CLINICAL RELEVANCE OF PROTEINASE ACTIVATED RECEPTORS (PARS) IN THE GUT Gut, June 1, 2005; 54(6): 867 - 874. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Noorbakhsh, N. Vergnolle, J. C. McArthur, C. Silva, M. Vodjgani, P. Andrade-Gordon, M. D. Hollenberg, and C. Power Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection J. Immunol., June 1, 2005; 174(11): 7320 - 7329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Holzhausen, L.C. Spolidorio, and N. Vergnolle Proteinase-activated Receptor-2 (PAR2) Agonist Causes Periodontitis in Rats Journal of Dental Research, February 1, 2005; 84(2): 154 - 159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Steinhoff, J. Buddenkotte, V. Shpacovitch, A. Rattenholl, C. Moormann, N. Vergnolle, T. A. Luger, and M. D. Hollenberg Proteinase-Activated Receptors: Transducers of Proteinase-Mediated Signaling in Inflammation and Immune Response Endocr. Rev., February 1, 2005; 26(1): 1 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Masamune, K. Kikuta, M. Satoh, N. Suzuki, and T. Shimosegawa Protease-Activated Receptor-2-Mediated Proliferation and Collagen Production of Rat Pancreatic Stellate Cells J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 651 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K Chan, N. Vergnolle, M. D Hollenberg, and P.-Y. von der Weid Proteinase-activated receptor 2 activation modulates guinea-pig mesenteric lymphatic vessel pacemaker potential and contractile activity J. Physiol., October 15, 2004; 560(2): 563 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Cenac, A. C. Chin, R. Garcia-Villar, C. Salvador-Cartier, L. Ferrier, N. Vergnolle, A. G. Buret, J. Fioramonti, and L. Bueno PAR2 activation alters colonic paracellular permeability in mice via IFN-{gamma}-dependent and -independent pathways J. Physiol., August 1, 2004; 558(3): 913 - 925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kawabata, T. Kanke, D. Yonezawa, T. Ishiki, M. Saka, M. Kabeya, F. Sekiguchi, S. Kubo, R. Kuroda, M. Iwaki, et al. Potent and Metabolically Stable Agonists for Protease-Activated Receptor-2: Evaluation of Activity in Multiple Assay Systems in Vitro and in Vivo J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1098 - 1107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Amadesi, J. Nie, N. Vergnolle, G. S. Cottrell, E. F. Grady, M. Trevisani, C. Manni, P. Geppetti, J. A. McRoberts, H. Ennes, et al. Protease-Activated Receptor 2 Sensitizes the Capsaicin Receptor Transient Receptor Potential Vanilloid Receptor 1 to Induce Hyperalgesia J. Neurosci., May 5, 2004; 24(18): 4300 - 4312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Cottrell, S. Amadesi, E. F. Grady, and N. W. Bunnett Trypsin IV, a Novel Agonist of Protease-activated Receptors 2 and 4 J. Biol. Chem., April 2, 2004; 279(14): 13532 - 13539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. S. OSSOVSKAYA and N. W. BUNNETT Protease-Activated Receptors: Contribution to Physiology and Disease Physiol Rev, April 1, 2004; 84(2): 579 - 621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zhao and T. Shea-Donohue PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors Am J Physiol Gastrointest Liver Physiol, October 1, 2003; 285(4): G696 - G703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Chin, N. Vergnolle, W. K. MacNaughton, J. L. Wallace, M. D. Hollenberg, and A. G. Buret Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability PNAS, September 16, 2003; 100(19): 11104 - 11109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Cenac, R. Garcia-Villar, L. Ferrier, M. Larauche, N. Vergnolle, N. W. Bunnett, A.-M. Coelho, J. Fioramonti, and L. Bueno Proteinase-Activated Receptor-2-Induced Colonic Inflammation in Mice: Possible Involvement of Afferent Neurons, Nitric Oxide, and Paracellular Permeability J. Immunol., April 15, 2003; 170(8): 4296 - 4300. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
