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Glucocorticoid Availability in Colonic Inflammation of Rat

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Abstract

Recent in vitro studies have shown the involvement of pro-inflammatory cytokines in the regulation of the local metabolism of glucocorticoids via 11β-hydroxysteroid dehydrogenase type 1 and type 2 (11HSD1 and 11HSD2). However, direct in vivo evidence for a relationship among the local metabolism of glucocorticoids, inflammation and steroid enzymes is still lacking. We have therefore examined the changes in the local metabolism of glucocorticoids during colonic inflammation induced by TNBS and the consequences of corticosterone metabolism inhibition by carbenoxolone on 11HSD1, 11HSD2, cyclooxygenase 2 (COX-2), mucin 2 (MUC-2), tumor necrosis factor α (TNF-α), and interleukin 1β (IL-1β). The metabolism of glucocorticoids was measured in tissue slices in vitro and their 11HSD1, 11HSD2, COX-2, MUC-2, TNF-α, and IL-1β mRNA abundances by quantitative reverse transcription-polymerase chain reaction. Colitis produced an up-regulation of colonic 11HSD1 and down-regulation of 11HSD2 in a dose-dependent manner, and these changes resulted in a decreased capacity of the inflamed tissue to inactivate tissue corticosterone. Similarly, 11HSD1 transcript was increased in colonic intraepithelial lymphocytes of TNBS-treated rats. Topical intracolonic application of carbenoxolone stimulated 11HSD1 mRNA and partially inhibited 11HSD2 mRNA and tissue corticosterone inactivation and these changes were blocked by RU-486. The administration of budesonide mimicked the effect of carbenoxolone. In contrast to the local metabolism of glucocorticoids, carbenoxolone neither potentiates nor diminishes gene expression for COX-2, TNF-α, and IL-1β, despite the fact that budesonide down-regulated all of them. These data indicate that inflammation is associated with the down-regulation of tissue glucocorticoid catabolism. However, these changes in the local metabolism of glucocorticoids do not modulate the expression of COX-2, TNF-α, and IL-1β in inflamed tissue.

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References

  1. Besedovsky HO, del Rey A (1996) Immune-neuro-endocrine interactions: facts and hypotheses. Endocr Rev 17:64–102

    Article  PubMed  CAS  Google Scholar 

  2. Wilckens T, De Rijk R (1997) Glucocorticoids and immune function: unknown dimensions and new frontier. Immunol Today 18:418–424

    Article  PubMed  CAS  Google Scholar 

  3. Stewart PM, Krozowski ZS (1999) 11β-hydroxysteroid dehydrogenase. Vit Horm 57:249–324

    Article  CAS  Google Scholar 

  4. Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Laverty GG, Cooper MS, Hewison M, Stewart PM (2004) 11β-hydroxysteroid dehydrogenase type 1: a tissue specific regulator of glucocorticoid response. Endocr Rev 25:831–866

    Article  PubMed  CAS  Google Scholar 

  5. Escher G, Galli I, Vishwanath BS, Frey BM, Frey FJ (1997) Tumor necrosis factor α and interleukin 1β enhance the corticone/cortisol shuttle. J Exp Med 186:189–198

    Article  PubMed  CAS  Google Scholar 

  6. Feinstein MB, Schleimer RP (1999) Regulation of the action of hydrocorticone in airway epithelial cells by 11β-hydroxysteroid dehydrogenase. Am J Respir Cell Mol Biol 21:403–408

    PubMed  CAS  Google Scholar 

  7. Suzuki S, Koyama K, Darnel A, Ishibashi H, Kobayashi S, Kubo H, Suzuki T, Sasano H, Krozowski ZS (2003) Dexamethasone upregulates 11β-hydroxysteroid dehydrogenase type 2 in BEAS-2B cells. Am J Respir Crit Care Med 167:1244–1249

    Article  PubMed  Google Scholar 

  8. Suzuki S, Matsuda Y, Sugawara T, Tabata T, Ishibashi H, Hoshikawa Y, Kubo H, Kondo T (2004) Effects of carbenoxolone on alveolar fluid clearance and lung inflammation in the rat. Crit Care Med 32:1910–1915

    Article  PubMed  CAS  Google Scholar 

  9. Tomlinson JW, Moore J, Cooper MS, Bujalska I, Shahmanesh M, Burt C, Strain A, Hewison M, Stewart PM (2001) Regulation of expression of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines. Endocrinology 142:1982–1989

    Article  PubMed  CAS  Google Scholar 

  10. Heiniger CD, Rochat MK, Frey FJ, Frey BM (2001) TNF-α enhances intracellular glucocorticoid availability. FEBS Lett 507:351–356

    Article  PubMed  CAS  Google Scholar 

  11. Cooper MS, Bujalska I, Rabbitt E, Walker EA, Bland R, Sheppard MC, Hewison M, Stewart PM (2001) Modulation of 11β-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. J Bone Miner Res 16:1037–1044

    Article  PubMed  CAS  Google Scholar 

  12. Yong PYK, Harlow C, Thong CJ, Hillier SG (2002) Regulation of 11β-hydroxysteroid dehydrogenase type 1 gene expression in human ovarian surface epithelial cells by interleukin-1. Human Reprod 9:2300–2306

    Article  Google Scholar 

  13. Suzuki S, Tsubochi H, Ishibashi H, Matsuda Y, Suzuki T, Krozowski ZS, Sasano H, Kondo T (2005) Inflammatory mediators down-regulate 11β-hydroxysteroid dehydrogenase type 2 in a human lung epithelial cell line BEAS-2B and rat lung. Tohoku J Exp Med 207:293–301

    Article  PubMed  CAS  Google Scholar 

  14. Pácha J, Mikšík I, Lisá V, Pohlová I (1997) Hormonal regulation of intestinal 11β-hydroxysteroid dehydrogenase. Life Sci 61:2391–2396

    Article  PubMed  Google Scholar 

  15. Bryndová J, Žbánková Š, Kment M, Pácha J (2004) Colitis up-regulates local glucocorticoid activation and down-regulates inactivation in colonic tissue. Scand J Gastroenterol 39:549–553

    Article  PubMed  CAS  Google Scholar 

  16. Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL (1989) Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 96:795–803

    PubMed  CAS  Google Scholar 

  17. Erdbäcker S, Andersson P, Lindberg C, Paulson J, Ryrfeldt A, Thalen A (1987) Liver metabolism of budesonide in rat, mouse, and man. comparative aspects. Drug Metab Dispos 15:403–411

    Google Scholar 

  18. Lyscom N, Brueton MJ (1982) Intraepithelial, lamina propria and peyer's patch lymphocytes of the rat small intestine: isolation and characterization in terms of immunoglobulin markers and receptors for monoclonal antibodies. Immunology 45:775–783

    PubMed  CAS  Google Scholar 

  19. Pácha J, Mikšík I (1996) 11β-hydroxysteroid dehydrogenase in developing rat intestine. J Endocrinol 148:561–566

    Article  PubMed  Google Scholar 

  20. Pácha J, Mikšík I, Mrnka L, Zemanová Z, Bryndová J, Mazancová K, Kučka M (2004) Corticosteroid regulation of colonic ion transport during postnatal development: methods for corticosterone analysis. Physiol Res 53:S63-S80

    PubMed  Google Scholar 

  21. Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78:206–209

    Article  PubMed  CAS  Google Scholar 

  22. Zhang TY, Ding X, Daynes RA (2005) The expression of 11β-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities. J Immunol 174:879–889

    PubMed  CAS  Google Scholar 

  23. Rachmilewitz D, Simon PL, Schwartz LW, Griswold DE, Fondacaro JD, Wasserman MA (1989) Inflammatory mediators of experimental colitis in rats. Gastroenterology 97:326–337

    PubMed  CAS  Google Scholar 

  24. Neurath MF, Becker C, Barbulescu K (1998) Role of NF-κB in immune and inflammatory responses in the gut. Gut 43:856–860

    Article  PubMed  CAS  Google Scholar 

  25. Reed KL, Fruin AB, Gower AC, Gonzales KD, Stucchi AF, Andry CD, O’Brien M, Becker JM (2005) NF-κB activation precedes increases in mRNA encoding neurokinin-1 receptor, proinflammatory cytokines, and adhesion molecules in dextran sulfate sodium-induced colitis in rats. Dig Dis Sci 50:2366–2378

    Article  PubMed  CAS  Google Scholar 

  26. Andrianifahanana M, Moniaux N, Batra SK (2006) Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases. Biochim Biophys Acta 1765:189–222

    PubMed  CAS  Google Scholar 

  27. van der Velden VH (1998) Glucocorticoids: mechanisms of action and anti-inflammatory potential in asthma. Mediators Inflamm 7:229–237

    Article  PubMed  Google Scholar 

  28. Pelissier MA, Muller C, Hill M, Morfin R (2006) Protection against dextran sodium sulfate-induced colitis by dehydroepiandrosterone and 7α-hydroxy-dehydroepiandrosterone in the rat. Steroids 71:240–248

    Article  PubMed  CAS  Google Scholar 

  29. Whorwood CB, Ricketts ML, Stewart PM (1994) Epithelial cell localization of type 2 11β-hydroxysteroid dehydrogenase in rat and human colon. Endocrinology 135:2533–2541

    Article  PubMed  CAS  Google Scholar 

  30. Thieringer R, Le Grand CB, Carbin L, Cai T-Q, Wong B, Wright SD, Hermanowski-Vosatka A (2001) 11β-hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation to macrophages. J Immunol 167:30–35

    PubMed  CAS  Google Scholar 

  31. Sun K, Myatt L (2003) Enhancement of glucocorticoid-induced 11β-hydroxysteroid dehydrogenase type 1 expression by proinflammatory cytokines in cultured human amnion fibroblasts. Endocrinology 144:5568–5577

    Article  PubMed  CAS  Google Scholar 

  32. Hardy DB, Pereria LE, Yang K (1999) Prostaglandins and leukotriene B4 are potent inhibitors of 11β-hydroxysteroid dehydrogenase type 2 activity in human choriocarcinoma JEG-3 cells. Biol Reprod 61:40–45

    Article  PubMed  CAS  Google Scholar 

  33. Patel FA, Clifton VL, Chwalisz K, Challis JR (1999) Steroid regulation of prostaglandin dehydrogenase activity and expression in human term placenta and chorio-decidua in relation to labor. J Clin Endocrinol Metab 84:291–299

    Article  PubMed  CAS  Google Scholar 

  34. Peskar BM, Holland A, Peskar BA (1976) Effect of carbenoxolone on prostaglandin synthesis and degradation. J Pharm Pharmacol 28:146–148

    PubMed  CAS  Google Scholar 

  35. Darnel AD, Archem TK, Yang K (1999) Regulation of 11β-hydroxysteroid dehydrogenase type 2 by steroid hormones and epidermal growth factor in the Ishikawa human endometrial cell line. J Steroid Biochem Mol Biol 70:203–210

    Article  PubMed  CAS  Google Scholar 

  36. Goppelt-Struebe M (1997) Molecular mechanisms involved in the regulation of prostaglandin biosynthesis by glucocorticoids. Biochem Pharmacol 53:1389–1395

    Article  PubMed  CAS  Google Scholar 

  37. Nakase H, Okazaki K, Tabata Y, Uose S, Ohana M, Uchida K, Nishi T, Debreceni A, Itoh T, Kawanami C, Iwano M, Ikada Y (2001) An oral drug delivery system targeting immune-regulating cells ameliorates mucosal injury in trinitrobenzene sulfonic acid-induced colitis. J Pharmacol Exp Ther 297:1122–1128

    PubMed  CAS  Google Scholar 

  38. Smith JW, Castro GA (1978) Relation of peroxidase activity in gut mucosa to inflammation. Am J Physiol 234:R72-R79

    PubMed  CAS  Google Scholar 

  39. Palmen MJHJ, Dieleman LA, Soesatyo M, Pena AS, Meuwissen SGM, van Rees EP (1998) Effects of local budesonide treatment on the cell-mediated immune response in acute and relapsing colitis in rats. Dig Dis Sci 43:2518–2525

    Article  PubMed  CAS  Google Scholar 

  40. Hoebler C, Gaudier E, De Coppet P, Rival M, Cherbut C (2006) MUC genes are differently expressed during onset and maintenance of inflammation in dextran sodium sulfate-treated mice. Dig Dis Sci 51:381–389

    Article  PubMed  CAS  Google Scholar 

  41. Jarry A, Vallette G, Branka JE, Laboisse C (1996) Direct secretory effect of interleukin-1 via type I receptors in human colonic mucous epithelial cells (HT29-C1.16E). Gut 38:240–242

    Article  PubMed  CAS  Google Scholar 

  42. Trompette A, Blanchard C, Zoghbi S, Bara J, Claustre J, Jourdan G, Chayvialle JA, Plaisance P (2004) The DHE cell line as a model for studying rat gastro-intestinal mucin expression: effects of dexamethasone. Eur J Cell Biol 83:347–358

    Article  PubMed  CAS  Google Scholar 

  43. Yoshimitsu M, Hayamizu K, Egi H, Okiyama J, Okajima M, Itamoto T, Asahara T (2006) The neutrophil/Th1 lymphocyte balance and the therapeutic effect of granulocyte colony-stimulating factor in TNBS-induced colitis of rat strains. J Interferon Cytokine Res 26:291–300

    Article  PubMed  CAS  Google Scholar 

  44. Togawa J-I, Nagase H, Tanaka K, Inamori M, Umezawa T, Nakajima A, Naito M, Sato S, Saito T, Sekihara H (2002) Lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine inbalance. Am J Physiol 283:G187-G195

    CAS  Google Scholar 

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Acknowledgments

This study was supported by the Ministry of Health (grant NR/8576–3), the Czech Science Foundation (305/07/0328) and Charles University (grant no. 77/2006 C). The authors are grateful to Mrs. I. Mezteková for technical assistance.

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Authors and Affiliations

  1. Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20, Prague 4-Krč, The Czech Republic

    P. Ergang, P. Leden, J. Bryndová, Š. Žbánková, I. Mikšík & J. Pácha

  2. Department of Medicine, Third Faculty of Medicine, Charles University, Prague, The Czech Republic

    P. Leden, Š. Žbánková & M. Kment

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  1. P. Ergang
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  2. P. Leden
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Correspondence to J. Pácha.

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Ergang, P., Leden, P., Bryndová, J. et al. Glucocorticoid Availability in Colonic Inflammation of Rat. Dig Dis Sci 53, 2160–2167 (2008). https://doi.org/10.1007/s10620-007-0125-6

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