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Carbachol induces TGF-alpha expression and colonic epithelial cell proliferation in sensory-desensitised rats

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Abstract

Objective/background

Signals for the expression of the peptide growth factors epidermal growth factor and transforming growth factor-α (TGFα) in the gastrointestinal mucosa are largely unknown. We have shown earlier that extrinsic afferents in the gastrointestinal tract induce TGFα expression in colonic mucosa via the deliberation of neurotransmitters substance P and calcitonin gene-related peptide. The aim of our present study was to determine the effects of carbachol on mucosal TGFα expression and epithelial cell proliferation in vivo.

Design/methods

Rats were divided in three groups. Group 1 was treated with vehicle only, group 2 received one single subcutaneous injection of 250 μg/kg of carbachol and animals in group 3 were sensory-desensitised prior to the injection of 250 μg/kg carbachol. TGFα expression and epithelial cell proliferation was evaluated by polymerase chain reaction, Western blot analysis and bromodeoxyuridine staining.

Results

Carbachol induced a significant increase in mucosal epithelial cell proliferation and TGFα expression. Sensory desensitisation did neither abolish the increased TGFα expression nor the increase in epithelial cell proliferation.

Conclusion

Parasympathetic pathways are involved in the control of TGFα expression in gastrointestinal mucosa as well as in epithelial cell proliferation.

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References

  1. Luck MS, Bass P (1993) Effect of epidermal growth factor on experimental colitis in the rat. J Pharmacol Exp Ther 264:984–990

    CAS  PubMed  Google Scholar 

  2. Procaccino F, Reinshagen M, Hoffmann P, Zeeh JM, Lakshmanan J, McRoberts JA, Patel A, French S, Eysselein VE (1994) Protective effect of epidermal growth factor in an experimental model of colitis in rats. Gastroenterology 107:12–17

    CAS  PubMed  Google Scholar 

  3. Wu SQ, Zhu WY, Yu JR (1993) Submaxillary gland epidermal growth factor accelerated healing of chronic gastric mucosal lesions in rats. Sheng Li Xue Bao 45:575–580

    CAS  PubMed  Google Scholar 

  4. Konturek SJ, Dembinski A, Warzecha Z, Brzozowski T, Gregory H (1988) Role of epidermal growth factor in healing of chronic gastroduodenal ulcers in rats. Gastroenterology 94:1300–1307

    CAS  PubMed  Google Scholar 

  5. Tepperman BL, Kiernan JA, Soper BD (1989) The effect of sialoadenectomy on gastric mucosal integrity in the rat: roles of epidermal growth factor and prostaglandin E2. Can J Physiol Pharmacol 67:1512–1519

    CAS  PubMed  Google Scholar 

  6. Egger B, Procaccino F, Lakshmanan J, Reinshagen M, Hoffmann P, Patel A, Reuben W, Gnanakkan S, Liu L, Barajas L, Eysselein VE (1997) Mice lacking transforming growth factor alpha have an increased susceptibility to dextran sulfate-induced colitis. Gastroenterology 113:825–832

    Article  CAS  PubMed  Google Scholar 

  7. Egger B, Buchler MW, Lakshmanan J, Moore P, Eysselein VE (2000) Mice harboring a defective epidermal growth factor receptor (waved-2) have an increased susceptibility to acute dextran sulfate-induced colitis. Scand J Gastroenterol 35:1181–1187

    Article  CAS  PubMed  Google Scholar 

  8. Egger B, Carey HV, Procaccino F, Chai NN, Sandgren EP, Lakshmanan J, Buslon VS, French SW, Buchler MW, Eysselein VE (1998) Reduced susceptibility of mice overexpressing transforming growth factor alpha to dextran sodium sulphate induced colitis. Gut 43:64–70

    CAS  PubMed  Google Scholar 

  9. Sinha A, Nightingale J, West KP, Berlanga-Acosta J, Playford RJ (2003) Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 349:350–357

    Article  CAS  PubMed  Google Scholar 

  10. Polk WH Jr, Dempsey PJ, Russell WE, Brown PI, Beauchamp RD, Barnard JA, Coffey RJ Jr (1992) Increased production of transforming growth factor alpha following acute gastric injury. Gastroenterology 102:1467–1474

    CAS  PubMed  Google Scholar 

  11. Hoffmann P, Zeeh JM, Lakshmanan J, Wu VS, Procaccino F, Reinshagen M, McRoberts JA, Eysselein VE (1997) Increased expression of transforming growth factor alpha precursors in acute experimental colitis in rats. Gut 41:195–202

    Article  CAS  PubMed  Google Scholar 

  12. Sottili M, Sternini C, Brecha NC, Lezoche E, Walsh JH (1992) Transforming growth factor alpha receptor binding sites in the canine gastrointestinal tract. Gastroenterology 103:1427–1436

    CAS  PubMed  Google Scholar 

  13. Sottili M, Sternini C, Reinshagen M, Brecha NC, Nast CC, Walsh JH, Eysselein VE (1995) Up-regulation of transforming growth factor alpha binding sites in experimental rabbit colitis. Gastroenterology 109:24–31

    Article  CAS  PubMed  Google Scholar 

  14. Hoffmann P, Reinshagen M, Zeeh JM, Lakshmanan J, Wu VS, Goebell H, Gerken G, Eysselein VE (2000) Increased expression of epidermal growth factor-receptor in an experimental model of colitis in rats. Scand J Gastroenterol 35:1174–1180

    Article  CAS  PubMed  Google Scholar 

  15. Mendelsohn J (1990) Anti-epidermal growth factor receptor monoclonal antibodies as potential anti-cancer agents. J Steroid Biochem Mol Biol 37:889–892

    Article  CAS  PubMed  Google Scholar 

  16. Carpenter G, Cohen S (1979) Epidermal growth factor. Annu Rev Biochem 48:193–216

    Article  CAS  PubMed  Google Scholar 

  17. Anderson BK, Karnes WE, Pearson RK (1994) Bile acids regulate the growth rate of transformed colonic epithelium and increase TGF-alpha mRNA levels. Gastroenterology 54:A384

    Google Scholar 

  18. Hoffmann P, Mazurkiewicz J, Holtmann G, Gerken G, Eysselein VE, Goebell H (2002) Capsaicin-sensitive nerve fibres induce epithelial cell proliferation, inflammatory cell immigration and transforming growth factor-alpha expression in the rat colonic mucosa in vivo. Scand J Gastroenterol 37:414–422

    Article  CAS  PubMed  Google Scholar 

  19. Bulut K, Felderbauer P, Hoeck K, Schmidt WE, Hoffmann P (2008) Increased duodenal expression of transforming growth factor-alpha and epidermal growth factor during experimental colitis in rats. Eur J Gastroenterol Hepatol 20:989–994

    Article  CAS  PubMed  Google Scholar 

  20. Horikawa Y, Shatos MA, Hodges RR, Zoukhri D, Rios JD, Chang EL, Bernardino CR, Rubin PA, Dartt DA (2003) Activation of mitogen-activated protein kinase by cholinergic agonists and EGF in human compared with rat cultured conjunctival goblet cells. Invest Ophthalmol Vis Sci 44:2535–2544

    Article  PubMed  Google Scholar 

  21. McCole DF, Keely SJ, Coffey RJ, Barrett KE (2002) Transactivation of the epidermal growth factor receptor in colonic epithelial cells by carbachol requires extracellular release of transforming growth factor-alpha. J Biol Chem 277:42603–42612

    Article  CAS  PubMed  Google Scholar 

  22. Phillips TE (1992) Both crypt and villus intestinal goblet cells secrete mucin in response to cholinergic stimulation. Am J Physiol 262:G327–G331

    CAS  PubMed  Google Scholar 

  23. Reinshagen M, Patel A, Sottili M, French S, Sternini C, Eysselein VE (1996) Action of sensory neurons in an experimental at colitis model of injury and repair. Am J Physiol 270:G79–G86

    CAS  PubMed  Google Scholar 

  24. Holzer P (1991) Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 43:143–201

    CAS  PubMed  Google Scholar 

  25. Liu L, Barajas L (1993) The rat renal nerves during development. Anat Embryol (Berl) 188:345–361

    CAS  Google Scholar 

  26. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  CAS  PubMed  Google Scholar 

  27. Ishidoya S, Morrissey J, McCracken R, Klahr S (1996) Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive nephropathy. Kidney Int 49:1110–1119

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76:4350–4354

    Article  CAS  PubMed  Google Scholar 

  30. Reinshagen M, Geerling I, Lakshmanan J, Rohm H, Lutz MP, Soinila S, Eysselein VE, Adler G (1997) Commercial mouse and human nerve growth factors contain nerve growth factor prohormone isoforms. J Neurosci Methods 76:75–81

    Article  CAS  PubMed  Google Scholar 

  31. Kiba T, Tanaka K, Hoshino M, Numata K, Okano K, Inoue S (1995) Ventromedial hypothalamic lesions induce the proliferation of gastrointestinal mucosal cells in the rat. Life Sci 57:827–832

    Article  CAS  PubMed  Google Scholar 

  32. Yoshimura R, Omori H, Somekawa S, Osaka T, Ito R, Inoue S, Endo Y (2006) Continuous carbachol infusion promotes peripheral cell proliferation and mimics vagus hyperactivity in a rat model of hypothalamic obesity. Biomed Res 27:81–88

    Article  CAS  PubMed  Google Scholar 

  33. Frucht H, Jensen RT, Dexter D, Yang WL, Xiao Y (1999) Human colon cancer cell proliferation mediated by the M3 muscarinic cholinergic receptor. Clin Cancer Res 5:2532–2539

    CAS  PubMed  Google Scholar 

  34. Ukegawa JI, Takeuchi Y, Kusayanagi S, Mitamura K (2003) Growth-promoting effect of muscarinic acetylcholine receptors in colon cancer cells. J Cancer Res Clin Oncol 129:272–278

    CAS  PubMed  Google Scholar 

  35. Derynck R (1986) Transforming growth factor-alpha: structure and biological activities. J Cell Biochem 32:293–304

    Article  CAS  PubMed  Google Scholar 

  36. Taylor P (1990) Cholinergic agonists. In: Goodman Gilman A, Rall TW, Bues AS, Taylor P (eds) The pharmacological basis of therapeutics. Pergamon, New York, pp 122–130

    Google Scholar 

  37. Kelly SM, Hunter JO (1990) Epidermal growth factor stimulates synthesis and secretion of mucus glycoproteins in human gastric mucosa. Clin Sci (Lond) 79:425–427

    CAS  Google Scholar 

  38. McLeay LM, Comeskey MA, Waters MJ (1990) Effects of epidermal growth factor on gastrointestinal electromyographic activity of conscious sheep. J Endocrinol 124:109–115

    Article  CAS  PubMed  Google Scholar 

  39. Rhodes JA, Tam JP, Finke U, Saunders M, Bernanke J, Silen W, Murphy RA (1986) Transforming growth factor alpha inhibits secretion of gastric acid. Proc Natl Acad Sci USA 83:3844–3846

    Article  CAS  PubMed  Google Scholar 

  40. Dembinski A, Drozdowicz D, Gregory H, Konturek SJ, Warzecha Z (1986) Inhibition of acid formation by epidermal growth factor in the isolated rabbit gastric glands. J Physiol 378:347–357

    CAS  PubMed  Google Scholar 

  41. Hui WM, Chen BW, Kung AW, Cho CH, Luk CT, Lam SK (1993) Effect of epidermal growth factor on gastric blood flow in rats: possible role in mucosal protection. Gastroenterology 104:1605–1610

    CAS  PubMed  Google Scholar 

  42. Code RA, Seroogy KB, Fallon JH (1987) Some transforming growth factor-alpha connections and their colocalization with enkephalin in the rat central nervous system. Brain Res 421:401–405

    Article  CAS  PubMed  Google Scholar 

  43. Hoffmann P, Zeeh JM, Lakshmanan J, Liu L, Cooray D, Barajas L, Eysselein VE (1997) Transforming growth factor alpha-immunoreactivity in neural tissues of the rat stomach. Regul Pept 69:121–125

    Article  CAS  PubMed  Google Scholar 

  44. Lazar LM, Blum M (1992) Regional distribution and developmental expression of epidermal growth factor and transforming growth factor-alpha mRNA in mouse brain by a quantitative nuclease protection assay. J Neurosci 12:1688–1697

    CAS  PubMed  Google Scholar 

  45. Yasui W, Ji ZQ, Kuniyasu H, Ayhan A, Yokozaki H, Ito H, Tahara E (1992) Expression of transforming growth factor alpha in human tissues: immunohistochemical study and Northern blot analysis. Virchows Arch A Pathol Anat Histopathol 421:513–519

    Article  CAS  PubMed  Google Scholar 

  46. Fisher DA, Lakshmanan J (1990) Metabolism and effects of epidermal growth factor and related growth factors in mammals. Endocr Rev 11:418–442

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine I, St. Josef Hospital, Ruhr-University of Bochum, Bochum, Germany

    Kerem Bulut, Peter Felderbauer & Wolfgang E. Schmidt

  2. Department of Internal Medicine I, Kliniken Essen-Mitte, Huyssens-Stiftung, Henricistraße 92, 45136, Essen, Germany

    Karoline Hoeck & Peter Hoffmann

Authors
  1. Kerem Bulut
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  2. Peter Felderbauer
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  3. Karoline Hoeck
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  4. Wolfgang E. Schmidt
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  5. Peter Hoffmann
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Corresponding author

Correspondence to Peter Hoffmann.

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Bulut, K., Felderbauer, P., Hoeck, K. et al. Carbachol induces TGF-alpha expression and colonic epithelial cell proliferation in sensory-desensitised rats. Int J Colorectal Dis 25, 335–341 (2010). https://doi.org/10.1007/s00384-009-0856-2

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  • DOI: https://doi.org/10.1007/s00384-009-0856-2

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