Skip to main content

Advertisement

SpringerLink
Log in

FK506-Binding Protein 5 mRNA Levels in Ileal Mucosa Are Associated with Pouchitis in Patients with Ulcerative Colitis

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Although the pathogenesis of pouchitis is incompletely understood, steroid and FK506 therapy are significantly associated with pouchitis. These medical treatments are regulated by the FK506-binding protein (FKBP) 4 and FKBP5 genes.

Aim

This study aimed to evaluate the relationship between pouchitis and FKBP4 and FKBP5 mRNA expression in ileal mucosa at the time of colectomy.

Methods

Ileal mucosa specimens were collected from 71 patients who underwent ileal pouch-anal anastomosis for ulcerative colitis. FKBP4 and FKBP5 mRNA expression was evaluated. The relationship between mRNA expression and clinicopathological factors, including developed pouchitis, was investigated.

Results

Of these 71 patients, 25 (35.2 %) patients developed pouchitis in a mean duration of 20.2 months (range 0–68 months). FKBP4 mRNA levels in patients who received an immunomodulator were significantly higher than those in untreated patients (0.167 ± 0.060 vs 0.131 ± 0.065, p = 0.009). However, FKBP5 mRNA levels in patients who received a three-stage operation were significantly lower than those in the other patients (1.97 ± 1.15 vs 2.70 ± 1.12, p = 0.02). A total dose of prednisolone >9.4 g (HR 2.84, p = 0.02) before colectomy and FKBP5 mRNA level higher than the median (HR 4.49, p = 0.01) were identified as factors related to pouchitis.

Conclusions

FKBP5 mRNA levels in ileal mucosa at the time of colectomy are significantly associated with pouchitis and may be a predictive factor for developing pouchitis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Shen B, Fazio VW, Remzi FH, et al. Comprehensive evaluation of inflammatory and noninflammatory sequelae of ileal pouch-anal anastomoses. Am J Gastroenterol. 2005;100:93–101.

    Article  PubMed  Google Scholar 

  2. Kalkan IH, Dagli U, Onder FO, et al. Evaluation of preoperative predictors of development of pouchitis after ileal-pouch-anastomosis in ulcerative colitis. Clin Res Hepatol Gastroenterol. 2012;36:622–627.

    Article  CAS  PubMed  Google Scholar 

  3. Okita Y, Araki T, Tanaka K, et al. Predictive factors for development of chronic pouchitis after ileal pouch-anal anastomosis in ulcerative colitis. Digestion. 2013;88:101–109.

    Article  PubMed  Google Scholar 

  4. Baumgart DC, Wiedenmann B, Dignass AU. Rescue therapy with tacrolimus is effective in patients with severe and refractory inflammatory bowel disease. Aliment Pharmacol Ther. 2003;17:1273–1281.

    Article  CAS  PubMed  Google Scholar 

  5. Baumgart DC, Pintoffl JP, Sturm A, et al. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease—a long-term follow-up. Am J Gastroenterol. 2006;101:1048–1056.

    Article  CAS  PubMed  Google Scholar 

  6. Ng SC, Arebi N, Kamm MA. Medium-term results of oral tacrolimus treatment in refractory inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:129–134.

    Article  PubMed  Google Scholar 

  7. Harding MW, Galat A, Uehling DE, et al. A receptor for the immunosuppressant FK506 is a cis–trans peptidyl-prolyl isomerase. Nature. 1989;341:758–760.

    Article  CAS  PubMed  Google Scholar 

  8. Galigniana NM, Ballmer LT, Toneatto J, et al. Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51. J Neurochem. 2012;122:4–18.

    Article  CAS  PubMed  Google Scholar 

  9. Riggs DL, Roberts PJ, Chirillo SC, et al. The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo. EMBO J. 2003;22:1158–1167.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Denny WB, Valentine DL, Reynolds PD, et al. Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology. 2000;141:4107–4113.

    CAS  PubMed  Google Scholar 

  11. Marz AM, Fabian AK, Kozany C, et al. Large FK506-binding proteins shape the pharmacology of rapamycin. Mol Cell Biol. 2013;33:1357–1367.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Baughman G, Wiederrecht GJ, Campbell NF, et al. FKBP51, a novel T-cell-specific immunophilin capable of calcineurin inhibition. Mol Cell Biol. 1995;15:4395–4402.

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34:S186–S195.

    Article  CAS  PubMed  Google Scholar 

  14. Shen B, Achkar JP, Connor JT, et al. Modified pouchitis disease activity index: a simplified approach to the diagnosis of pouchitis. Dis Colon Rectum. 2003;46:748–753.

    Article  PubMed  Google Scholar 

  15. Hashavia E, Dotan I, Rabau M, et al. Risk factors for chronic pouchitis after ileal pouch-anal anastomosis: a prospective cohort study. Colorectal Dis. 2012;14:1365–1371.

    Article  CAS  PubMed  Google Scholar 

  16. Coffey JC, Rowan F, Burke J, et al. Pathogenesis of and unifying hypothesis for idiopathic pouchitis. Am J Gastroenterol. 2009;104:1013–1023.

    Article  PubMed  Google Scholar 

  17. Lohmuller JL, Pemberton JH, Dozois RR, et al. Pouchitis and extraintestinal manifestations of inflammatory bowel disease after ileal pouch-anal anastomosis. Ann Surg. 1990;211:622–629.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Fleshner P, Ippoliti A, Dubinsky M, et al. A prospective multivariate analysis of clinical factors associated with pouchitis after ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol. 2007;5:952–958.

    Article  PubMed  Google Scholar 

  19. Achkar JP, Al-Haddad M, Lashner B, et al. Differentiating risk factors for acute and chronic pouchitis. Clin Gastroenterol Hepatol. 2005;3:60–66.

    Article  PubMed  Google Scholar 

  20. Hata K, Watanabe T, Shinozaki M, et al. Patients with extraintestinal manifestations have a higher risk of developing pouchitis in ulcerative colitis: multivariate analysis. Scand J Gastroenterol. 2003;38:1055–1058.

    Article  CAS  PubMed  Google Scholar 

  21. Lipman JM, Kiran RP, Shen B, et al. Perioperative factors during ileal pouch-anal anastomosis predict pouchitis. Dis Colon Rectum. 2011;54:311–317.

    Article  PubMed  Google Scholar 

  22. Penna C, Dozois R, Tremaine W, et al. Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis. Gut. 1996;38:234–239.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Wasmuth HH, Trano G, Endreseth BH, et al. Primary sclerosing cholangitis and extraintestinal manifestations in patients with ulcerative colitis and ileal pouch-anal anastomosis. J Gastrointest Surg. 2010;14:1099–1104.

    Article  PubMed  Google Scholar 

  24. Hoda KM, Collins JF, Knige KL, et al. Predictors of pouchitis after ileal pouch-anal anastomosis: a retrospective review. Dis Colon Rectum. 2008;51:554–560.

    Article  PubMed  Google Scholar 

  25. Shen B, Yu C, Lian L, et al. Prediction of late-onset pouch failure in patients with restorative proctocolectomy with a nomogram. J Crohn’s Colitis. 2012;6:198–206.

    Article  Google Scholar 

  26. Toiyama Y, Araki T, Yoshiyama S, et al. Secondary pouchitis in a post-operative patient with ulcerative colitis, successfully treated by salvage surgery. World J Gastroenterol. 2005;11:6888–6890.

    PubMed  Google Scholar 

  27. Banasiewicz T, Marciniak R, Kaczmarek E, et al. The diameter of the ileal J-pouch-anal anastomosis as an important risk factor of pouchitis—clinical observations. Med Sci Monit. 2011;17:CR91–CR96.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Madden MV, McIntyre AS, Nicholls RJ. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis. Dig Dis Sci. 1994;39:1193–1196.

    Article  CAS  PubMed  Google Scholar 

  29. Shen B, Achkar JP, Lashner BA, et al. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis. Inflamm Bowel Dis. 2001;7:301–305.

    Article  CAS  PubMed  Google Scholar 

  30. Mimura T, Rizzello F, Helwig U, et al. Four-week open-label trial of metronidazole and ciprofloxacin for the treatment of recurrent or refractory pouchitis. Aliment Pharmacol Ther. 2002;16:909–917.

    Article  CAS  PubMed  Google Scholar 

  31. Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology. 2003;124:1202–1209.

    Article  PubMed  Google Scholar 

  32. Gosselink MP, Schouten WR, van Lieshout LM, et al. Delay of the first onset of pouchitis by oral intake of the probiotic strain Lactobacillus rhamnosus GG. Dis Colon Rectum. 2004;47:876–884.

    Article  PubMed  Google Scholar 

  33. Sambuelli A, Boerr L, Negreira S, et al. Budesonide enema in pouchitis—a double-blind, double-dummy, controlled trial. Aliment Pharmacol Ther. 2002;16:27–34.

    Article  CAS  PubMed  Google Scholar 

  34. O’Donnell S, O’Morain CA. Therapeutic benefits of budesonide in gastroenterology. Ther Adv Chronic Dis. 2010;1:177–186.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Schouten WR. Pouchitis. Mediat Inflamm. 1998;7:175–181.

    Article  CAS  Google Scholar 

  36. Lee RS, Tamashiro KL, Yang X, et al. Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice. Endocrinology. 2010;151:4332–4343.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Mostaghel EA, Page ST, Lin DW, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007;67:5033–5041.

    Article  CAS  PubMed  Google Scholar 

  38. Jaaskelainen T, Makkonen H, Palvimo JJ. Steroid up-regulation of FKBP51 and its role in hormone signaling. Curr Opin Pharmacol. 2011;11:326–331.

    Article  PubMed  Google Scholar 

  39. Woodruff PG, Boushey HA, Dolganov GM, et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA. 2007;104:15858–15863.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Hawkins GA, Lazarus R, Smith RS, et al. The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids. J Allergy Clin Immunol. 2009;123:1376–1383.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Riggs DL, Cox MB, Tardif HL, et al. Noncatalytic role of the FKBP52 peptidyl-prolyl isomerase domain in the regulation of steroid hormone signaling. Mol Cell Biol. 2007;27:8658–8669.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Schulke JP, Wochnik GM, Lang-Rollin I, et al. Differential impact of tetratricopeptide repeat proteins on the steroid hormone receptors. PLoS One. 2010;5:e11717.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Matsushita R, Hashimoto A, Tomita T, et al. Enhanced expression of mRNA for FK506-binding protein 5 in bone marrow CD34 positive cells in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:87–90.

    CAS  PubMed  Google Scholar 

  44. Issaeva I, Zonis Y, Rozovskaia T, et al. Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol Cell Biol. 2007;27:1889–1903.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Lang AE, Ernst K, Lee H, et al. The chaperone Hsp90 and PPIases of the cyclophilin and FKBP families facilitate membrane translocation of Photorhabdus luminescens ADP-ribosyltransferases. Cell Microbiol. 2014;16:490–503.

    Article  CAS  PubMed  Google Scholar 

  46. Kaiser E, Bohm N, Ernst K, et al. FK506-binding protein 51 interacts with Clostridium botulinum C2 toxin and FK506 inhibits membrane translocation of the toxin in mammalian cells. Cell Microbiol. 2012;14:1193–1205.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Toru Ogura Ph.D. (Clinical Research Support Center, Mie University Hospital) for her critical comments and suggestions on the statistical analysis.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Toshimitsu Araki, Mikio Kawamura, Koji Tanaka, Yoshiki Okita, Hiroyuki Fujikawa, Keiichi Uchida, Yuji Toiyama, Yasuhiro Inoue, Yasuhiko Mohri & Masato Kusunoki

Authors
  1. Toshimitsu Araki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mikio Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koji Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshiki Okita
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroyuki Fujikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Keiichi Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuji Toiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yasuhiro Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasuhiko Mohri
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masato Kusunoki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshimitsu Araki.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Araki, T., Kawamura, M., Tanaka, K. et al. FK506-Binding Protein 5 mRNA Levels in Ileal Mucosa Are Associated with Pouchitis in Patients with Ulcerative Colitis. Dig Dis Sci 60, 1617–1623 (2015). https://doi.org/10.1007/s10620-015-3528-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-015-3528-9

Keywords

Search

Navigation