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Localization of TFF3 peptide in human esophageal submucosal glands and gastric cardia: differentiation of two types of gastric pit cells along the rostro-caudal axis

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Abstract

TFF3 (trefoil factor family 3), which is a major secretory product of the gastric antrum and the intestine, but which is nearly absent in the gastric corpus, plays a key role in the maintenance of mucosal integrity. Here, we have systematically investigated TFF3 expression in the esophagus and gastric cardia by the use of reverse transcription/polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Synthesis of TFF3, but not TFF1 or TFF2, is detectable in esophageal submucosal glands. The stratified squamous epithelium is devoid of TFF synthesis. Prominent TFF3 expression starts at the Z-line with a sharply decreasing gradient toward the cardia. Immunohistochemistry has localized TFF3 to surface mucous cells of the proximal cardia. TFF3 distribution differs characteristically from that of TFF1 (secreted primarily by superficial surface mucous cells), whereas TFF3, together with the mucin MUC5AC, is also found in deeper lying cells toward the isthmus. This is the first report of TFF3 as a typical secretory peptide of esophageal submucosal glands and gastric cardia. The different expression patterns of TFF3 and TFF1 in the cardia suggest a stepwise maturation of surface mucous cells from TFF3/MUC5AC-positive cells close to the isthmus to TFF1/TFF3/MUC5AC-positive cells at the pit. The gradient of TFF3 expression along the gastric rostro-caudal axis defines two types of gastric pit cells: those secreting TFF3 in the cardia and the antrum and those nearly devoid of TFF3 synthesis in the corpus. This indicates the special requirement, particularly of the esophagogastric junction, for TFF3-triggered protection and repair.

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References

  • Arul GS, Moorghen M, Myerscough N, Alderson DA, Spicer RD, Corfield AP (2000) Mucin gene expression in Barrett’s oesophagus: an in situ hybridisation and immunhistochemical study. Gut 47:753–761

    Article  PubMed  CAS  Google Scholar 

  • Barrett MT, Yeung KY, Ruzzo WL, Hsu L, Blount PL, Sullivan R, Zarbl H, Delrow J, Rabinovitch PS, Reid BJ (2002) Transcriptional analyses of Barrett’s metaplasia and normal upper GI mucosae. Neoplasia 4:121–128

    Article  PubMed  Google Scholar 

  • Baus-Loncar M, Kayademir T, Takaishi S, Wang T (2005) Trefoil factor family 2 deficiency and immune response. Cell Mol Life Sci 62:2947–2955

    Article  PubMed  CAS  Google Scholar 

  • Brittan M, Wright NA (2004) The gastrointestinal stem cell. Cell Prolif 37:35–53

    Article  PubMed  CAS  Google Scholar 

  • Cliffe LJ, Humphreys NE, Lane TE, Potten CS, Booth C, Grencis RK (2005) Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 308:1463–1465

    Article  PubMed  CAS  Google Scholar 

  • DeNardi FG, Riddell RH (1997) Esophagus. In: Sternberg SS (ed) Histology for pathologists. Lippincott-Raven, Philadelphia, pp 461–480

    Google Scholar 

  • Devine DA, High AS, Owen PJ, Poulsom R, Bonass WA (2000) Trefoil factor expression in normal and diseased human salivary glands. Hum Pathol 31:509–515

    Article  PubMed  CAS  Google Scholar 

  • Dixon MF, Genta RM, Yardley JH, Correa P, Participants of the International Workshop on the Histology of Gastritis (1996) Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 20:1161–1181

    Article  PubMed  CAS  Google Scholar 

  • Fitzgerald RC, Farthing MJG (2003) The pathogenesis of Barrett’s esophagus. Gastrointest Endoscopy Clin 13:233–255

    Article  Google Scholar 

  • Fox CA, Sapinoso LM, Zhang H, Zhang W, McLeod HL, Petroni GR, Mullick T, Moskaluk CA, Frierson HF, Hampton GM, Powell SM (2005) Altered expression of TFF-1 and CES-2 in Barrett’s esophagus and associated adenocarcinomas. Neoplasia 7:407–416

    Article  PubMed  CAS  Google Scholar 

  • Guillem P, Billeret V, Buisine MP, Flejou JF, Lecomte-Houcke M, Degand P, Aubert JP, Triboulet JP, Porchet N (2000) Mucin gene expression and cell differentiation in human normal, premalignant and malignant esophagus. Int J Cancer 88:856–861

    Article  PubMed  CAS  Google Scholar 

  • Hanby AM, Poulsom R, Singh S, Jeffery RE, Wright N (1993) Spasmolytic polypeptide is a major antral peptide: distribution of the trefoil peptides human spasmolytic polypeptide and pS2 in the stomach. Gastroenterology 105:1110–1116

    PubMed  CAS  Google Scholar 

  • Hanby AM, Jankowski JAZ, Elia G, Poulsom R, Wright NA (1994) Expression of the trefoil peptides pS2 and human spasmolytic polypeptide (hSP) in Barrett’s metaplasia and the native esophageal epithelium: delineation of epithelial phenotype. J Pathol 173:213–219

    Article  PubMed  CAS  Google Scholar 

  • Hoffmann W (2005) TFF (trefoil factor family) peptide-triggered signals promoting mucosal restitution. Cell Mol Life Sci 62:2932–2938

    Article  PubMed  CAS  Google Scholar 

  • Hoffmann W (2006) TFF (trefoil factor family) peptides. In: Kastin AJ (ed) Handbook of biologically active peptides. Elsevier, San Diego, pp 1147–1154

    Google Scholar 

  • Hoffmann W, Jagla W (2002) Cell type specific expression of secretory TFF-peptides: co-localization with mucins and synthesis in the brain. Int Rev Cytol 213:147–181

    Article  PubMed  CAS  Google Scholar 

  • Hoffmann W, Jagla W, Wiede A (2001) Molecular medicine of TFF-peptides: from gut to brain. Histol Histopathol 16:319–334

    PubMed  CAS  Google Scholar 

  • Jagla W, Wiede A, Kölle S, Hoffmann W (1998) Differential expression of the TFF-peptides xP1 and xP4 in the gastrointestinal tract of Xenopus laevis. Cell Tissue Res 291:13–18

    Article  PubMed  CAS  Google Scholar 

  • Jagla W, Wiede A, Hinz M, Dietzmann K, Gülicher D, Gerlach KL, Hoffmann W (1999) Secretion of TFF-peptides by human salivary glands. Cell Tissue Res 298:161–166

    Article  PubMed  CAS  Google Scholar 

  • Jakowlew SB, Breathnach R, Jeltsch JM, Masiakowski P, Chambon P (1984) Sequence of the pS2 mRNA induced by estrogen in the human breast cancer cell line MCF-7. Nucleic Acids Res 12:2861–2878

    Article  PubMed  CAS  Google Scholar 

  • Karam SM (1999) Lineage commitment and maturation of epithelial cells in the gut. Front Biosci 4:286–298

    Google Scholar 

  • Karam S, Leblond CP (1993) Dynamics of epithelial cells in the corpus of the mouse stomach. II. Outward migration of pit cells. Anat Rec 236:280–296

    Article  PubMed  CAS  Google Scholar 

  • Karam S, Leblond CP (1995) Origin and migratory pathways of the eleven epithelial cell types present in the body of the mouse stomach. Microsc Res Tech 31:193–214

    Article  PubMed  CAS  Google Scholar 

  • Karam SM, Straiton T, Hassan WM, Leblond CP (2003) Defining epithelial cell progenitors in the human oxyntic mucosa. Stem Cells 21:322–336

    Article  PubMed  Google Scholar 

  • Karam SM, Tomasetto C, Rio MC (2004) Trefoil factor 1 is required for the commitment programme of mouse oxyntic epithelial progenitors. Gut 53:1408–1415

    Article  PubMed  CAS  Google Scholar 

  • Kouznetsova I, Peitz U, Vieth M, Meyer F, Vestergaard EM, Malfertheiner P, Roessner A, Lippert H, Hoffmann W (2004) A gradient of TFF3 (trefoil factor family 3) peptide synthesis within the normal human gastric mucosa. Cell Tissue Res 316:155–165

    Article  PubMed  CAS  Google Scholar 

  • Labouvie C, Machado JC, Carneiro F, Sarbia M, Vieth M, Porschen R, Seitz G, Blin N (1999) Differential expression of mucins and trefoil peptides in native epithelium, Barrett’s metaplasia and squamous cell carcinoma of the esophagus. J Cancer Res Clin Oncol 125:71–76

    Article  PubMed  CAS  Google Scholar 

  • Lee ER (1985) Dynamic histology of the antral epithelium in the mouse stomach. III. Ultrastructure and renewal of pit cells. Am J Anat 172:225–240

    Article  PubMed  CAS  Google Scholar 

  • Mashimo H, Wu DC, Podolsky DK, Fishman MC (1996) Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 274:262–265

    Article  PubMed  CAS  Google Scholar 

  • Mills JC, Andersson N, Hong CV, Stappenbeck TS, Gordon JI (2002) Molecular characterization of mouse gastric epithelial progenitor cells. Proc Natl Acad Sci USA 99:14819–14824

    Article  PubMed  CAS  Google Scholar 

  • Nomura S, Kaminishi M, Sugiyama K, Oohara T, Esumi H (1996) Clonal analysis of isolated single fundic and pyloric gland of stomach using X-linked polymorphism. Biochem Biophys Res Commun 226:385–390

    Article  PubMed  CAS  Google Scholar 

  • Oien KA, Vass JK, Downie I, Fullarton G, Keith WN (2003) Profiling, comparison and validation of gene expression in gastric carcinoma and normal stomach. Oncogene 22:4287–4300

    Article  PubMed  CAS  Google Scholar 

  • Patel S, Rew DA, Taylor I, Potten CS, Owen C, Roberts SA (1993) Study of the proliferation in human gastric mucosa after in vivo bromodeoxyuridine labelling. Gut 34:893–896

    PubMed  CAS  Google Scholar 

  • Peitz U, Kouznetsova I, Wex T, Gebert I, Vieth M, Roessner A, Hoffmann W, Malfertheiner P (2004) TFF3 expression at the esophagogastric junction is increased in gastro-esophageal reflux disease (GERD). Peptides 25:771–777

    Article  PubMed  CAS  Google Scholar 

  • Playford RJ (1995) Peptides and gastrointestinal mucosal integrity. Gut 37:595–597

    PubMed  CAS  Google Scholar 

  • Playford RJ, Ghosh S, Mahmood A (2004) Growth factors and trefoil peptides in gastrointestinal health and disease. Curr Opin Pharmacol 4:567–571

    Article  PubMed  CAS  Google Scholar 

  • Podolsky DK, Lynch-Devaney K, Stow JL, Oates P, Murgue B, De-Beaumont M, Sands BE, Mahida YR (1993) Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion. J Biol Chem 268:6694–6702

    PubMed  CAS  Google Scholar 

  • Poulsen SS, Kissow H, Hare K, Hartmann B, Thim L (2005) Luminal and parenteral TFF2 and TFF3 dimer and monomer in two models of experimental colitis in the rat. Regul Pept 26:163–171

    Article  CAS  Google Scholar 

  • Probst JC, Skutella T, Müller-Schmid A, Jirikowski GF, Hoffmann W (1995) Molecular and cellular analysis of rP1.B in the rat hypothalamus: in situ hybridization and immunohistochemistry of a new P-domain neuropeptide. Mol Brain Res 33:269–276

    Article  PubMed  CAS  Google Scholar 

  • Rio MC, Bellocq JP, Daniel JY, Tomasetto C, Lathe R, Chenard MP, Batzenschlager A, Chambon P (1988) Breast cancer-associated pS2 protein: synthesis and secretion by normal stomach mucosa. Science 241:705–708

    Article  PubMed  CAS  Google Scholar 

  • Sampliner RE (2002) Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 97:1888–1895

    Article  PubMed  Google Scholar 

  • Sarosiek J, McCallum RW (2000) Mechanisms of oesophageal mucosal defence. Baillière’s Clin Gastroenterol 14:701–717

    CAS  Google Scholar 

  • Taupin D, Podolsky DK (2003) Trefoil factors: initiators of mucosal healing. Nat Rev 4:721–733

    Article  CAS  Google Scholar 

  • van Baal JWPM, Milano F, Baal Rygiel AM, Bergman JJGHM, Rosmolen WD, Deventer SJH van, Wang KK, Peppelenbosch MP, Krishnadath KK (2005) A comparative analysis by SAGE of gene expression profiles of Barrett’s esophagus, normal squamous esophagus, and gastric cardia. Gastroenterology 129:1274–1281

    Article  PubMed  CAS  Google Scholar 

  • Van de Bovenkamp JHB, Korteland-Van Male AM, Warson C, Büller HA, Einerhand AWC, Ectors NLEY, Dekker J (2003) Gastric-type mucin and TFF-peptide expression in Barrett’s oesophagus is disturbed during increased expression of MUC2. Histopathol 42:555–565

    Article  Google Scholar 

  • Vandenbroucke K, Hans W, Huysse J van, Neirynck S, Demetter P, Remaut E, Rottiers P, Steidler L (2004) Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice. Gastroenterology 127:502–513

    Article  PubMed  CAS  Google Scholar 

  • Vermeer PD, Einwalter LA, Moninger TO, Rokhlina T, Kern JA, Zabner J, Welsh MJ (2003) Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 422:322–326

    Article  PubMed  CAS  Google Scholar 

  • Von Herbay A, Rudi J (2000) Role of apoptosis in gastric epithelial turnover. Microsc Res Tech 48:303–311

    Article  Google Scholar 

  • Wang TC, Goldenring JR (2002) Inflammation intersection: gp130 balances gut irritation and stomach cancer. Nat Med 8:1080–1082

    Article  PubMed  CAS  Google Scholar 

  • Warson C, Van de Bovenkamp JHB, Korteland-van Male AM, Büller HA, Einerhand AWC, Ectors NLEY, Dekker J (2002) Barrett’s esophagus is characterized by expression of gastric-type mucins (MUC5AC, MUC6) and TFF peptides (TFF1 and TFF2), but the risk of carcinoma development may be indicated by the intestinal-type mucin, MUC2. Hum Pathol 33:660–668

    Article  PubMed  CAS  Google Scholar 

  • Wiede A, Jagla W, Welte T, Köhnlein T, Busk H, Hoffmann W (1999) Localization of TFF3, a new mucus-associated peptide of the human respiratory tract. Am J Respir Crit Care Med 159:1330–1335

    PubMed  CAS  Google Scholar 

  • Wong WM, Poulsom R, Wright NA (1999) Trefoil peptides. Gut 44:890–895

    Article  PubMed  CAS  Google Scholar 

  • Wright NA (2000) Epithelial stem cell repertoire in the gut: clues to the origin of cell lineages, proliferative units and cancer. Int J Exp Path 81:117–143

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Dr. K. Rutkowski for her help in generating the polyclonal anti-TFF1 antisera, and Dr. J. Lindquist for comments on the manuscript.

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Authors and Affiliations

  1. Institut für Molekularbiologie und Medizinische Chemie, Universitätsklinikum, Otto-von-Guericke-Universität Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany

    Irina Kouznetsova & Werner Hoffmann

  2. Institut für Pathologie, Otto-von-Guericke-Universität Magdeburg, 39120, Magdeburg, Germany

    Thomas Kalinski, Michael Vieth & Albert Roessner

  3. Klinik für Gastroenterologie, Hepatologie und Infektiologie, Otto-von-Guericke-Universität Magdeburg, 39120, Magdeburg, Germany

    Ulrich Peitz, Klaus E. Mönkemüller & Peter Malfertheiner

  4. Medizinisch-Naturwissenschaftliches Forschungszentrum, Eberhard-Karls-Universität Tübingen, 72074, Tübingen, Germany

    Hubert Kalbacher

  5. Klinik für Chirurgie, Otto-von-Guericke-Universität Magdeburg, 39120, Magdeburg, Germany

    Frank Meyer & Hans Lippert

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  1. Irina Kouznetsova
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  2. Thomas Kalinski
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  3. Ulrich Peitz
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  4. Klaus E. Mönkemüller
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  7. Frank Meyer
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  8. Albert Roessner
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  9. Peter Malfertheiner
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  11. Werner Hoffmann
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Correspondence to Werner Hoffmann.

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This work was supported by grant 01ZZ0107/PP13 from the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (to W.H.), by grants 0163615 and 0500058 from the Fonds der Chemischen Industrie (to W.H.), and by a grant from the Medical Faculty (PP4).

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Kouznetsova, I., Kalinski, T., Peitz, U. et al. Localization of TFF3 peptide in human esophageal submucosal glands and gastric cardia: differentiation of two types of gastric pit cells along the rostro-caudal axis. Cell Tissue Res 328, 365–374 (2007). https://doi.org/10.1007/s00441-006-0350-x

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