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International Journal of Colorectal Disease

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01-01-2006 | Original Article

Blocking MAdCAM-1 in vivo reduces leukocyte extravasation and reverses chronic inflammation in experimental colitis

Authors: Stefan Farkas, Matthias Hornung, Christine Sattler, Karoline Edtinger, Markus Steinbauer, Matthias Anthuber, Hans J. Schlitt, Hans Herfarth, Edward K. Geissler

Published in: International Journal of Colorectal Disease | Issue 1/2006

Abstract

Background

Leukocyte recruitment to sites of intestinal inflammation is a crucial multi-step process, leading ultimately to the accumulation of cells in the inflamed tissue. These interactions in the gut are critically dependent on the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed on endothelial cells within the mesenteric lymph nodes and the lamina propria of the intestine. Here, we investigate the pathophysiologic role of MAdCAM-1 in the intestinal microcirculation in vivo.

Methods

Using a standard mouse model, chronic colitis was established after four cycles of dextran sodium sulfate (DSS) application. MAdCAM-1 expression was investigated by immunohistochemistry and Western blotting, as well as real-time polymerase chain reaction (PCR). Intravital microscopy was used to study the role of MAdCAM-1 on leukocyte-endothelium interactions and leukocyte extravasation.

Results

Significant changes in MAdCAM-1 were observed in mice with chronic DSS-induced colitis. Upregulation of MAdCAM-1 expression in chronic colitis was demonstrated on a protein and messenger ribonucleic acid (mRNA) level. Anti-MAdCAM-1 treatment lead to a marked reduction (>60%) of leukocyte sticking and extravasation in vivo, compared to the controls. This was parallelled by a significant reduction (45%) of intestinal inflammation, as measured by the histologic grading score.

Conclusion

These in vivo results demonstrate a distinct role of MAdCAM-1 in inflammatory intestinal diseases, and suggest that therapeutic strategies targeting this adhesion molecule could be useful in the treatment of chronic colitis.

Van Assche G, Rutgeerts P (2002) Antiadhesion molecule therapy in inflammatory bowel disease. Inflamm Bowel Dis 8:291–300

Guslandi M (1999) Microcirculation in inflammatory bowel diseases. Int J Colorectal Dis 14:265

Spiik AK, Ridderstad A, Axelsson LG, Midtvedt T, Bjork L, Pettersson S (2002) Abrogated lymphocyte infiltration and lowered CD14 in dextran sulfate induced colitis in mice treated with p65 antisense oligonucleotides. Int J Colorectal Dis 17:223–232

Farkas S, Herfarth H, Rossle M, Schroeder J, Steinbauer M, Guba M, Beham A, Scholmerich J, Jauch KW, Anthuber M (2001) Quantification of mucosal leucocyte endothelial cell interaction by in vivo fluorescence microscopy in experimental colitis in mice. Clin Exp Immunol 126:250–258

Warnock RA, Campbell JJ, Dorf ME, Matsuzawa A, McEvoy LM, Butcher EC (2000) The role of chemokines in the microenvironmental control of T versus B cell arrest in Peyer’s patch high endothelial venules. J Exp Med 191:77–88

Krieglstein CF, Anthoni C, Laukotter MG, Rijcken E, Spiegel HU, Senninger N, Schurmann G (1999) Effect of anti-CD11b (alphaM-MAC-1) and anti-CD54 (ICAM-1) monoclonal antibodies on indomethacin induced chronic ileitis in rats. Int J Colorectal Dis 14:219–223

Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, McEvoy LM, Butcher EC, Kassam N, Mackay CR, Newman W, Ringler DJ (1997) Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 151:97–110

Connor EM, Eppihimer MJ, Morise Z, Granger DN, Grisham MB (1999) Expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in acute and chronic inflammation. J Leukoc Biol 65:349–355

Kato S, Hokari R, Matsuzaki K, Iwai A, Kawaguchi A, Nagao S, Miyahara T, Itoh K, Ishii H, Miura S (2000) Amelioration of murine experimental colitis by inhibition of mucosal addressin cell adhesion molecule-1. J Pharmacol Exp Ther 295:183–189

10.

Fong S, Jones S, Renz ME, Chiu HH, Ryan AM, Presta LG, Jackson D (1997) Mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Its binding motif for alpha 4 beta 7 and role in experimental colitis. Immunol Res 16:299–311

11.

Shand A, Forbes A (2003) Potential therapeutic role for cytokine or adhesion molecule manipulation in Crohn’s disease: in the shadow of infliximab? Int J Colorectal Dis 18:1–11

12.

von Andrian UH, Mempel TR (2003) Homing and cellular traffic in lymph nodes. Nat Rev Immunol 3:867–878

13.

von Andrian UH, Engelhardt B (2003) Alpha4 integrins as therapeutic targets in autoimmune disease. N Engl J Med 348:68–72

14.

Stopfer P, Obermeier F, Dunger N, Falk W, Farkas S, Janotta M, Möller A, Männel DN (2004) Blocking lymphotoxin-β receptor activation diminishes inflammation via reduced mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression and leucocyte margination in chronic DSS-induced colitis. Clin Exp Immunol 136(1):21–29

15.

Shigematsu T, Specian RD, Wolf RE, Grisham MB, Granger DN (2001) MAdCAM mediates lymphocyte–endothelial cell adhesion in a murine model of chronic colitis. Am J Physiol Gasterointest Liver Physiol 281:G1309–G1315

16.

Soriano A, Salas A, Salas A, Sans M, Gironella M, Elena M, Anderson DC, Pique JM, Panes J (2000) VCAM-1, but not ICAM-1 or MAdCAM-1, immunoblockade ameliorates DSS-induced colitis in mice. Lab Invest 80:1541–1551

17.

Wittig BM, Zeitz M (2003) The gut as an organ of immunology. Int J Colorectal Dis 18:181–187

18.

Wirtz S, Neurath MF (2000) Animal models of intestinal inflammation: new insights into the molecular pathogenesis and immunotherapy of inflammatory bowel disease. Int J Colorectal Dis 15:144–160

19.

Obermeier F, Dunger N, Strauch UG, Grunwald N, Herfarth H, Scholmerich J, Falk W (2003) Contrasting activity of cytosin–guanosin dinucleotide oligonucleotides in mice with experimental colitis. Clin Exp Immunol 134:217–224

20.

Harris AG, Hecht R, Peer F, Nolte D, Messmer K (1997) An improved intravital microscopy system. Int J Microcirc Clin Exp 17:322–327

21.

Streeter PR, Berg EL, Rouse BT, Bargatze RF, Butcher EC (1988) A tissue-specific endothelial cell molecule involved in lymphocyte homing. Nature 331:41–46

22.

Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

23.

Overbergh L, Valckx D, Waer M, Mathieu C (1999) Quantification of murine cytokine mRNAs using real time quantitative reverse transcriptase PCR. Cytokine 11:305–312

24.

Feagan BG (2003) Maintenance therapy for inflammatory bowel disease. Am J Gastroenterol 98:S6–S17

25.

Sans M, Panes J, Ardite E, Elizalde JI, Arce Y, Elena M, Palacin A, Fernandez-Checa JC, Anderson DC, Lobb R, Pique JM (1999) VCAM-1 and ICAM-1 mediate leukocyte–endothelial cell adhesion in rat experimental colitis. Gastroenterology 116:874–883

26.

Soriano-Izquierdo A, Gironella M, Massaguer A, May FE, Salas A, Sans M, Poulsom R, Thim L, Piqu JM, Panes J (2003) Trefoil peptide TFF2 treatment reduces VCAM-1 expression and leukocyte recruitment in experimental intestinal inflammation. J Leukoc Biol 75:214–223

27.

Hokari R, Kato S, Matsuzaki K, Iwai A, Kawaguchi A, Nagao S, Miyahara T, Itoh K, Sekizuka E, Nagata H, Ishii H, Iizuka T, Miyasaka M, Miura S (2001) Involvement of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in the pathogenesis of granulomatous colitis in rats. Clin Exp Immunol 126:259–265

28.

Arihiro S, Ohtani H, Suzuki M, Murata M, Ejima C, Oki M, Kinouchi Y, Fukushima K, Sasaki I, Nakamura S, Matsumoto T, Torii A, Toda G, Nagura H (2002) Differential expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in ulcerative colitis and Crohn’s disease. Pathol Int 52:367–374

29.

Wright N, Hidalgo A, Rodriguez-Frade JM, Soriano SF, Mellado M, Parmo-Cabanas M, Briskin MJ, Teixido J (2002) The chemokine stromal cell-derived factor-1 alpha modulates alpha 4 beta 7 integrin-mediated lymphocyte adhesion to mucosal addressin cell adhesion molecule-1 and fibronectin. J Immunol 168:5268–5277

30.

Sasaki M, Bharwani S, Jordan P, Joh T, Manas K, Warren A, Harada H, Carter P, Elrod JW, Wolcott M, Grisham MB, Alexander JS (2003) The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin reduces disease activity and inflammation in dextran-sulfate induced colitis. J Pharmacol Exp Ther 305:78–85

31.

Kojouharoff G, Hans W, Obermeier F, Mannel DN, Andus T, Scholmerich J, Gross V, Falk W (1997) Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice. Clin Exp Immunol 107:353–358

32.

Obermeier F, Kojouharoff G, Hans W, Scholmerich J, Gross V, Falk W (1999) Interferon-gamma (IFN-gamma)- and tumour necrosis factor (TNF)-induced nitric oxide as toxic effector molecule in chronic dextran sulphate sodium (DSS)-induced colitis in mice. Clin Exp Immunol 116:238–245

33.

Myers KJ, Murthy S, Flanigan A, Witchell DR, Butler M, Murray S, Siwkowski A, Goodfellow D, Madsen K, Baker B (2003) Antisense oligonucleotide blockade of tumor necrosis factor-alpha in two murine models of colitis. J Pharmacol Exp Ther 304:411–424

34.

Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, Fiers W, Remaut E (2000) Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289:1352–1355

35.

Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98:694–702

Title: Blocking MAdCAM-1 in vivo reduces leukocyte extravasation and reverses chronic inflammation in experimental colitis
Authors: Stefan Farkas
Matthias Hornung
Christine Sattler
Karoline Edtinger
Markus Steinbauer
Matthias Anthuber
Hans J. Schlitt
Hans Herfarth
Edward K. Geissler
Publication date: 01-01-2006
Publisher: Springer-Verlag
Published in: International Journal of Colorectal Disease / Issue 1/2006
Print ISSN: 0179-1958
Electronic ISSN: 1432-1262
DOI: https://doi.org/10.1007/s00384-004-0709-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Blocking MAdCAM-1 in vivo reduces leukocyte extravasation and reverses chronic inflammation in experimental colitis

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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