Advertisement

International Journal of Colorectal Disease

, Volume 22, Issue 3, pp 303–312 | Cite as

(E)-metanicotine hemigalactarate (TC-2403-12) inhibits IL-8 production in cells of the inflamed mucosa

  • Tanja Spoettl
  • Christine Paetzel
  • Hans Herfarth
  • Merouane Bencherif
  • Juergen Schoelmerich
  • Roland Greinwald
  • Gregory J. Gatto
  • Gerhard Rogler
Original Article

Abstract

Background

Nicotine is of therapeutic value in ulcerative colitis, but its administration is connected with adverse events. Nicotine derivatives are currently being tested to maintain the therapeutic effects and minimize adverse events. TC-2403-12 is a (E)-metanicotine hemigalactarate. The aim of this study was to determine the effectiveness of TC-2403-12 in the inhibition of TNF- and lipopolysaccharide (LPS)-induced cell activation.

Methods

Colonic epithelial cells (CEC), monocytes (MM6), granulocytes, and the intestinal epithelial cell line HT-29 were stimulated with TNF and LPS and treated with TC-2403-12. IL-8 secretion in the cell supernatants and NF-κB activation were determined by ELISA. Apoptosis was quantified by flow cytometry.

Results

In MM6 cells, IL-8 secretion was significantly decreased to 30% of control after TC-2403-12 treatment, with best results after pretreatment for 24 h. This decrease in cell activation was not due to apoptosis and was not mediated by inhibition of NF-κB activation. IL-8 production in neutrophils and primary CEC also tended to be decreased after TC-2403-12 treatment. TC-2403-12 had no influence on IL-8 secretion of HT-29 cells.

Conclusion

TC-2403-12 effectively inhibited TNF- and LPS-induced IL-8 production in different cell types. No toxic effects occurred at the concentrations used. Preincubation of cells with TC-2403-12 showed the best effects.

Keywords

Nicotine derivatives Ulcerative colitis Interleukin-8 Mucosal inflammation Macrophages Epithelial cells 

References

  1. 1.
    van Kruiningen HJ, Colombel JF, Cartun RW, Whitlock RH, Koopmans M, Kangro HO, Hoogkamp-Korstanje JA, Lecomte-Houcke M, Devred M, Paris JC (1993) An in-depth study of Crohn’s disease in two French families. Gastroenterology 104:351–360PubMedGoogle Scholar
  2. 2.
    Andus T, Gross V (2000) Etiology and pathophysiology of inflammatory bowel disease—environmental factors. Hepatogastroenterology 47:29–43PubMedGoogle Scholar
  3. 3.
    Farrell RJ, Peppercorn MA (2002) Ulcerative colitis. Lancet 359:331–340CrossRefPubMedGoogle Scholar
  4. 4.
    Shanahan F (2002) Crohn’s disease. Lancet 359:62–69CrossRefPubMedGoogle Scholar
  5. 5.
    MacDermott RP (1999) Chemokines in the inflammatory bowel diseases. J Clin Immunol 19:266–272CrossRefPubMedGoogle Scholar
  6. 6.
    Robinson M (1998) Medical therapy of inflammatory bowel disease for the 21st century. Eur J Surg Suppl 164:90–98CrossRefGoogle Scholar
  7. 7.
    Lang KA, Peppercorn MA (1999) Promising new agents for the treatment of inflammatory bowel disorders. Drugs R D 1:237–244PubMedGoogle Scholar
  8. 8.
    de Castella H (1982) Non-smoking: a feature of ulcerative colitis. Br Med J (Clin Res Ed) 284:1706Google Scholar
  9. 9.
    Harries AD, Baird A, Rhodes J (1982) Non-smoking: a feature of ulcerative colitis. Br Med J (Clin Res Ed) 284:706Google Scholar
  10. 10.
    Somerville KW, Logan RF, Edmond M, Langman MJ (1984) Smoking and Crohn’s disease. Br Med J (Clin Res Ed) 289:954–956Google Scholar
  11. 11.
    Tobin MV, Logan RF, Langman MJ, McConnell RB, Gilmore IT (1987) Cigarette smoking and inflammatory bowel disease. Gastroenterology 93:316–321PubMedGoogle Scholar
  12. 12.
    Thomas GA, Rhodes J, Green JT (1998) Inflammatory bowel disease and smoking—a review. Am J Gastroenterol 93:144–149PubMedGoogle Scholar
  13. 13.
    Jarvik ME (1991) Beneficial effects of nicotine. Br J Addict 86:571–575CrossRefPubMedGoogle Scholar
  14. 14.
    Westman EC, Levin ED, Rose JE (1995) Nicotine as a therapeutic drug. N C Med J 56:48–51PubMedGoogle Scholar
  15. 15.
    Green JT, Richardson C, Marshall RW, Rhodes J, McKirdy HC, Thomas GA, Williams GT (2000) Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis. Aliment Pharmacol Ther 14:1429–1434CrossRefPubMedGoogle Scholar
  16. 16.
    Motley RJ, Rhodes J, Williams G, Tavares IA, Bennett A (1990) Smoking, eicosanoids and ulcerative colitis. J Pharm Pharmacol 42:288–289PubMedGoogle Scholar
  17. 17.
    Srivastava ED, Russell MA, Feyerabend C, Rhodes J (1990) Effect of ulcerative colitis and smoking on rectal blood flow. Gut 31:1021–1024PubMedGoogle Scholar
  18. 18.
    Cope GF, Heatley RV, Kelleher JK (1986) Smoking and colonic mucus in ulcerative colitis. Br Med J (Clin Res Ed) 293:481CrossRefGoogle Scholar
  19. 19.
    Prytz H, Benoni C, Tagesson C (1989) Does smoking tighten the gut? Scand J Gastroenterol 24:1084–1088PubMedGoogle Scholar
  20. 20.
    Arnott ID, Williams N, Drummond HE, Ghosh S (2002) Whole gut lavage fluid interleukin-1beta and interleukin-8 in smokers and non-smokers with Crohn’s disease in clinical remission. Dig Liver Dis 34:424–429CrossRefPubMedGoogle Scholar
  21. 21.
    Sher ME, Bank S, Greenberg R, Sardinha TC, Weissman S, Bailey B, Gilliland R, Wexner SD (1999) The influence of cigarette smoking on cytokine levels in patients with inflammatory bowel disease. Inflamm Bowel Dis 5:73–78PubMedCrossRefGoogle Scholar
  22. 22.
    Sandborn WJ, Tremaine WJ, Leighton JA, Lawson GM, Zins BJ, Compton RF, Mays DC, Lipsky JJ, Batts KP, Offord KP, Hurt RD, Green J (1999) Nicotine tartrate liquid enemas for mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy: a pilot study. Aliment Pharmacol Ther 11:663–671CrossRefGoogle Scholar
  23. 23.
    Papke RL, Webster JC, Lippiello PM, Bencherif M, Francis MM (2000) The activation and inhibition of human nicotinic acetylcholine receptor by RJR-2403 indicate a selectivity for the alpha4beta2 receptor subtype. J Neurochem 75:204–216CrossRefPubMedGoogle Scholar
  24. 24.
    Bencherif M, Lovette ME, Fowler KW, Arrington S, Reeves L, Caldwell WS, Lippiello PM (1996) RJR-2403: a nicotinic agonist with CNS selectivity I. In vitro characterization. J Pharmacol Exp Ther 279:1413–1421PubMedGoogle Scholar
  25. 25.
    Lippiello PM, Bencherif M, Gray JA, Peters S, Grigoryan G, Hodges H, Collins AC (1996) RJR-2403: a nicotinic agonist with CNS selectivity II. In vivo characterization. J Pharmacol Exp Ther 279:1422–1429PubMedGoogle Scholar
  26. 26.
    Rogler G, Daig R, Aschenbrenner E, Vogl D, Schlottmann K, Falk W, Gross V, Scholmerich J, Andus T (1998) Establishment of long-term primary cultures of human small and large intestinal epithelial cells. Lab Invest 78:889–890PubMedGoogle Scholar
  27. 27.
    Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T, Knuechel R, Baeuerle PA, Scholmerich J, Gross V (1998) Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 115:357–369CrossRefPubMedGoogle Scholar
  28. 28.
    Hogg RC, Bertrand D (2004) Nicotinic acetylcholine receptors as drug targets. Curr Drug Targets CNS Neurol Disord 3:123–130CrossRefPubMedGoogle Scholar
  29. 29.
    Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al Abed Y, Czura CJ, Tracey KJ (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384–388PubMedCrossRefGoogle Scholar
  30. 30.
    Summers AE, Whelan CJ, Parsons ME (2003) Nicotinic acetylcholine receptor subunits and receptor activity in the epithelial cell line HT29. Life Sci 72:2091–2094CrossRefPubMedGoogle Scholar
  31. 31.
    Zhou X, Ren J, Brown E, Schneider D, Caraballo-Lopez Y, Galligan JJ (2002) Pharmacological properties of nicotinic acetylcholine receptors expressed by guinea pig small intestinal myenteric neurons. J Pharmacol Exp Ther 302:889–897CrossRefPubMedGoogle Scholar
  32. 32.
    Wang Y, Pereira EF, Maus AD, Ostlie NS, Navaneetham D, Lei S, Albuquerque EX, Conti-Fine BM (2001) Human bronchial epithelial and endothelial cells express alpha7 nicotinic acetylcholine receptors. Mol Pharmacol 60:1201–1209PubMedGoogle Scholar
  33. 33.
    Carlson NG, Bacchi A, Rogers SW, Gahring LC (1998) Nicotine blocks TNF-a-mediated neuroprotection to NMDA by an a-bungarotoxin-sensitive pathway. J Neurobiol 35:29–36CrossRefPubMedGoogle Scholar
  34. 34.
    Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC (1999) Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol 163:3963–3968PubMedGoogle Scholar
  35. 35.
    Gijsbers K, Van Assche G, Joossens S, Struyf S, Proost P, Rutgeerts P, Geboes K, van Damme J (2004) CXCR1-binding chemokines in inflammatory bowel diseases: down-regulated IL-8/CXCL8 production by leukocytes in Crohn’s disease and selective GCP-2/CXCL6 expression in inflamed intestinal tissue. Eur J Immunol 34:1992–2000CrossRefPubMedGoogle Scholar
  36. 36.
    Banks C, Bateman A, Payne R, Johnson P, Sheron N (2003) Chemokine expression in IBD. Mucosal chemokine expression is unselectively increased in both ulcerative colitis and Crohn’s disease. J Pathol 199:28–35CrossRefPubMedGoogle Scholar
  37. 37.
    Daig R, Andus T, Aschenbrenner E, Falk W, Scholmerich J, Gross V (1996) Increased interleukin 8 expression in the colon mucosa of patients with inflammatory bowel disease. Gut 38:216–222PubMedGoogle Scholar
  38. 38.
    Kucharzik T, Williams IR (2002) Neutrophil migration across the intestinal epithelial barrier—summary of in vitro data and description of a new transgenic mouse model with doxycycline-inducible interleukin-8 expression in intestinal epithelial cells. Pathobiology 70:143–149CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Tanja Spoettl
    • 1
  • Christine Paetzel
    • 1
  • Hans Herfarth
    • 1
  • Merouane Bencherif
    • 3
  • Juergen Schoelmerich
    • 1
  • Roland Greinwald
    • 2
  • Gregory J. Gatto
    • 3
  • Gerhard Rogler
    • 1
  1. 1.Department of Internal Medicine IUniversity of RegensburgRegensburgGermany
  2. 2.Dr. FALK Pharma GmbHFreiburgGermany
  3. 3.TargaceptWinston-SalemUSA

Personalised recommendations