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The Expression of Protease-Activated Receptor 2 and 4 in the Colon of Irritable Bowel Syndrome Patients

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Abstract

Background

Irritable bowel syndrome (IBS) pathophysiology has not been fully understood. Abnormalities of serine proteases have been identified in IBS patients. In addition, protease-activated receptors (PAR) activation interferes with several components of the pathogenesis of IBS, so, evaluating the PAR expression in IBS patients may contribute to understanding the pathogenesis of the disease.

Aims

This study aimed to investigate whether the expression of PAR4 and PAR2 in the colon was changed in IBS patients and was associated with IBS.

Methods

Colon mucosal biopsies of 34 IBS patients (16 constipation- and 18 diarrhea-predominant) and 18 control subjects were collected. Gene transcripts of PAR2, PAR4, tryptase, and trypsin were quantified using real-time polymerase chain reaction (PCR) and the expression of PAR2 and PAR4 receptors was also measured by immunohistology and image analysis.

Results

In IBS patients, the mRNA expression of tryptase and trypsin normalized against β-actin gene was higher compared to control subjects (P < 0.001). No difference was observed in the PAR2 mRNA level or protein level between control subjects on the one hand and IBS patients or subgroups on the other. In IBS or IBS subgroups patients, the expression of PAR4 in the mRNA level or protein level was lower than the control subjects.

Conclusions

This study, for the first time, indicated the PAR4 expression in IBS patients. Decreased PAR4 expression may help us to understand the pathogenesis of IBS.

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References

  1. Drossman DA, Corazziari E, Delvaux M, et al. The functional gastrointestinal disorders. 3rd ed. Washington: Degnon; 2006.

    Google Scholar 

  2. Coughlin SR. How the protease thrombin talks to cells. Proc Natl Acad Sci USA. 1999;96:11023–11027.

    Article  PubMed  CAS  Google Scholar 

  3. Vergnolle N. Clinical relevance of proteinase activated receptors (PARs) in the gut. Gut. 2005;54:867–874.

    Article  PubMed  CAS  Google Scholar 

  4. Kawabata A, Kuroda R, Nishida M, et al. Protease-activated receptor-2 (PAR-2) in the pancreas and parotid gland: Immunolocalization and involvement of nitric oxide in the evoked amylase secretion. Life Sci. 2002;71:2435–2446.

    Article  PubMed  CAS  Google Scholar 

  5. Oikonomopoulou K, Hansen KK, Saifeddine M, et al. Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs). Biol Chem. 2006;387:817–824.

    Article  PubMed  CAS  Google Scholar 

  6. Vergnolle N. Modulation of visceral pain and inflammation by protease-activated receptors. Br J Pharmacol. 2004;141:1264–1274.

    Article  PubMed  CAS  Google Scholar 

  7. Lourbakos A, Yuan YP, Jenkins AL, et al. Activation of protease-activated receptors by gingipains from Porphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity. Blood. 2001;97:3790–3797.

    Article  PubMed  CAS  Google Scholar 

  8. Vergnolle N, Bunnett NW, Sharkey KA, et al. Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nat Med. 2001;7:821–826.

    Article  PubMed  CAS  Google Scholar 

  9. Cenac N, Andrews CN, Holzhausen M, et al. Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest. 2007;117:636–647.

    Article  PubMed  CAS  Google Scholar 

  10. Cenac N, Chin AC, Garcia-Villar R, et al. PAR2 activation alters colonic paracellular permeability in mice via IFN-gamma-dependent and -independent pathways. J Physiol. 2004;558:913–925.

    Article  PubMed  CAS  Google Scholar 

  11. Ramachandran R, Hollenberg MD. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br J Pharmacol. 2008;153:S263–S282.

    Article  PubMed  CAS  Google Scholar 

  12. Xu WF, Andersen H, Whitmore TE, et al. Cloning and characterization of human protease-activated receptor 4. Proc Natl Acad Sci USA. 1998;95:6642–6646.

    Article  PubMed  CAS  Google Scholar 

  13. Asfaha S, Cenac N, Houle S, et al. Protease-activated receptor-4: a novel mechanism of inflammatory pain modulation. Br J Pharmacol. 2007;150:176–185.

    Article  PubMed  CAS  Google Scholar 

  14. Augé C, Balz-Hara D, Steinhoff M, et al. Protease-activated receptor-4 (PAR 4): a role as inhibitor of visceral pain and hypersensitivity. Neurogastroenterol Motil. 2009;21:1189-e107.

    Article  PubMed  Google Scholar 

  15. Drossman DA, Dumitrascu DL. Rome III: new standard for functional gastrointestinal disorders. J Gastrointestin Liver Dis. 2006;15:237–241.

    PubMed  Google Scholar 

  16. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCt method. Methods. 2001;25:402–408.

    Article  PubMed  CAS  Google Scholar 

  17. Róka R, Wittmann T, Bueno L. Altered protease signalling in the gut: a novel pathophysiological factor in irritable bowel syndrome. Neurogastroenterol Motil. 2008;20:853–856.

    Article  PubMed  Google Scholar 

  18. Reed DE, Barajas-Lopez C, Cottrell G, et al. Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons. J Physiol. 2003; 547:531–542.

    Article  PubMed  CAS  Google Scholar 

  19. Coelho AM, Vergnolle N, Guiard B, et al. Proteinases and proteinase-activated receptor 2: a possible role to promote visceral hyperalgesia in rats. Gastroenterology. 2002;122:1035–1047.

    Article  PubMed  CAS  Google Scholar 

  20. Gecse K, Róka R, Ferrier L, et al. Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity. Gut. 2008;57:591–599.

    Article  PubMed  CAS  Google Scholar 

  21. Kawabata A, Kuroda R, Nagata N, et al. In vivo evidence that protease-activated receptors 1 and 2 modulate gastrointestinal transit in the mouse. Br J Pharmacol. 2001;133:1213–1218.

    Article  PubMed  CAS  Google Scholar 

  22. Róka R, Ait-Belgnaoui A, Salvador-Cartier C, et al. Dexamethasone prevents visceral hyperalgesia but not colonic permeability increase induced by luminal protease-activated receptor-2 agonist in rats. Gut. 2007;56:1072–1078.

    Article  PubMed  Google Scholar 

  23. Hansen KK, Sherman PM, Cellars L, et al. A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis. Proc Natl Acad Sci USA. 2005;102:8363–8368.

    Article  PubMed  CAS  Google Scholar 

  24. Jacob C, Yang PC, Darmoul D, et al. Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins. J Biol Chem. 2005;280:31936–31948.

    Article  PubMed  CAS  Google Scholar 

  25. Karanjia R, Spreadbury I, Bautista-Cruz F, et al. Activation of protease-activated receptor-4 inhibits the intrinsic excitability of colonic dorsal root ganglia neurons. Neurogastroenterol Motil. 2009;21:1218–1221.

    Article  PubMed  CAS  Google Scholar 

  26. Kawabata A, Kuroda R, Kuroki N, et al. Dual modulation by thrombin of the motility of rat oesophageal muscularis mucosae via two distinct protease-activated receptors (PARs): a novel role for PAR-4 as opposed to PAR-1. Br J Pharmacol. 2000;131:578–584.

    Article  PubMed  CAS  Google Scholar 

  27. Schmidlin F, Bunnett NW. Protease-activated receptors: how proteases signal to cells. Curr Opin Pharmacol. 2001;1:575–582.

    Article  PubMed  CAS  Google Scholar 

  28. Bian ZX, Li Z, Huang ZX, et al. Unbalanced expression of protease-activated receptors-1 and -2 in the colon of diarrhea-predominant irritable bowel syndrome patients. J Gastroenterol. 2009;44:666–674.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the Fundamental Research Funds for the Central Universities.

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Correspondence to Lei Dong.

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Zhao, Jh., Dong, L., Shi, Ht. et al. The Expression of Protease-Activated Receptor 2 and 4 in the Colon of Irritable Bowel Syndrome Patients. Dig Dis Sci 57, 58–64 (2012). https://doi.org/10.1007/s10620-011-1827-3

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  • DOI: https://doi.org/10.1007/s10620-011-1827-3

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