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Gene Review

Tff2  -  trefoil factor 2

Rattus norvegicus

Synonyms: SP, Sml1, Spasmolytic polypeptide, Trefoil factor 2
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Disease relevance of Tff2

  • Trefoil peptide TFF2 (spasmolytic polypeptide) potently accelerates healing and reduces inflammation in a rat model of colitis [1].
  • In nucleus basalis neurons, substance P (SP) causes a slow excitation, mediated through a pertussis toxin-insensitive G protein, by suppressing an inward rectifier K+ channel [2].
  • SP is the primary mediator of an axon reflex mediating neurogenic inflammation in the intestine [3].
  • Therefore, this study examines the effect of SP on capsaicin-induced mucosal hyperemia and mast cells [4].
  • Conversely, treatment with nerve growth factor (NGF) increased both ganglionic SP and total ganglion protein [5].

Psychiatry related information on Tff2

  • In these cells, the peak response latency was significantly longer to Ang II than to SP (59.5 +/- 4.7 versus 26.5 +/- 2.4 seconds, p less than 0.0001) [6].
  • Only (D-Pro4, D-Trp7,9,10) SP (4-11) was found to attenuate the drug-induced increases in motor activity, indicating that it is a substance P antagonist with activity in the CNS [7].
  • In the second experiment, a facilitation of inhibitory avoidance learning was obtained by injection of RA-octil or SP unilaterally into the basal forebrain immediately after the learning trial [8].
  • If SP is coreleased with acetylcholine, the additive actions of the two neurotransmitters might heighten the excitability of postsynaptic PRF neurons and ensure the initiation and maintenance of REM sleep [9].
  • In contrast, low pain threshold correlated with decreased IR-SP and IR-ME [10].

High impact information on Tff2

  • For example, footshock stress can activate rat mesocortical DA cells but does not alter nigrostriatal DA turnover, while also decreasing substance P (SP) concentrations in the midbrain interpeduncular nucleus and in the adjacent ventral tegmental area (VTA), but not in the substantia nigra (SN) [11].
  • SP antagonists now available are neurotoxic and of questionable efficacy, we therefore used monoclonal antibody against SP [11].
  • Veratridine prevented the increase in SP concentration in adult ganglia, and tetrodotoxin blocked the veratridine effect, suggesting that membrane depolarization and sodium influx prevented the rise in the SP content of adult ganglia as well as of neonatal ganglia [12].
  • The effect of age on the plasticity of the putative peptide neurotransmitter substance P (SP) was examined in the rat superior cervical sympathetic ganglion [12].
  • These results indicate that a diffusible messenger mediates the SP effect, that its signal transduction involves phosphorylation by PKC, and that dephosphorylation by a serine/threonine protein phosphatase mediates its recovery [2].

Chemical compound and disease context of Tff2


Biological context of Tff2


Anatomical context of Tff2

  • SP predominates in the gastric antrum as a 12 kDa form [22].
  • Both peptides are distributed in the apical secretory compartment of antral mucus cells (SP) and goblet cells (ITF), and on the lumenal surface [22].
  • Abundant SP immunoreactivity was seen in the lumen of the gastric glands and the mucus layer adherent to the gastric mucosa, indicating luminal secretion [17].
  • This study aimed to determine the structure and distribution of SP expression in the rat gastrointestinal tract [17].
  • The expression of SP in rats (rSP) was detected by RT-PCR in the intact mucosa and during all tested time periods reaching a peak at 4 h after the stress [23].

Associations of Tff2 with chemical compounds

  • In capsaicin-pretreated rats, the levels of substance P (SP) in bone marrow fluid were markedly reduced in comparison with the vehicle group (13.1+/-4.5pg/ml versus 47.3+/-5.5pg/ml, p<0.05) [24].
  • METHODS: Rats (n=8) were given either omeprazole (30 mg/kg per day; p.o.) or inert carrier for 1 week, and the effects on synthesis and peptide expression of the gastric trefoil peptides, TFF1/pS2 and TFF2/SP, were compared [19].
  • Preservation of mast cells in SP-treated rats was linearly correlated to increased mucosal blood flow after exposure to capsaicin [4].
  • This inhibitory action of SP was not blocked by atropine or hexamethonium, suggesting that a cholinergic mechanism was not involved [25].
  • RNase protection experiments indicated that the major message in the SCG is the beta-PPT mRNA, encoding both SP and neurokinin A peptide regions [26].

Regulatory relationships of Tff2


Other interactions of Tff2

  • Increased lung distension (due to CDH+TO) reduced expression of SP mRNAs and pro-SP-C and TTF-1 proteins and enhanced expression of RTI(40) (mRNA and protein; P < 0.05 for all) [18].
  • Distribution and metabolism of intravenously administered trefoil factor 2/porcine spasmolytic polypeptide in the rat [27].

Analytical, diagnostic and therapeutic context of Tff2

  • Expression of the SP peptide was localized by immunocytochemistry and Western blot analysis [17].
  • The trefoil pancreatic spasmolytic polypeptide (PSP) was tested for growth activity in vitro on epithelial cells and in vivo following intragastric or intravenous infusion in parenterally fed intact rats [28].
  • Much of the research into the localization of the spasmolytic polypeptide has relied on hybridization in situ to detect its mRNA, due to the absence of a suitable antibody [29].
  • Bilateral microinjections of the neurokinin-1 receptor antagonist [2-cyclopropoxy-5-(5-(trifluoromethyl)tetrazol-1-yl)benzyl]-(2-phenylpiperidin-3-yl)amine into the MeA blocked the stress-induced anxiogenic-like effect, supporting a functional significance of enhanced SP release [30].
  • Evidence for a potent inhibitory effect of SP on 5alpha-DHP and 3alpha,5alpha-THP formation in the SC was provided by combining pulse-chase experiments using [3H]progesterone as precursor, HPLC, recrystallization of [3H]metabolites to constant specific activity, and continuous flow detection of radioactive steroids [31].


  1. Trefoil peptide TFF2 (spasmolytic polypeptide) potently accelerates healing and reduces inflammation in a rat model of colitis. Tran, C.P., Cook, G.A., Yeomans, N.D., Thim, L., Giraud, A.S. Gut (1999) [Pubmed]
  2. Protein kinase C-mediated inhibition of an inward rectifier potassium channel by substance P in nucleus basalis neurons. Takano, K., Stanfield, P.R., Nakajima, S., Nakajima, Y. Neuron (1995) [Pubmed]
  3. Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum. Mantyh, C.R., Pappas, T.N., Lapp, J.A., Washington, M.K., Neville, L.M., Ghilardi, J.R., Rogers, S.D., Mantyh, P.W., Vigna, S.R. Gastroenterology (1996) [Pubmed]
  4. Substance P attenuates gastric mucosal hyperemia after stimulation of sensory neurons in the rat stomach. Grönbech, J.E., Lacy, E.R. Gastroenterology (1994) [Pubmed]
  5. Nerve growth factor stimulates the development of substance P in sensory ganglia. Kessler, J.A., Black, I.B. Proc. Natl. Acad. Sci. U.S.A. (1980) [Pubmed]
  6. Functional interactions between angiotensin II and substance P in the dorsal medulla. Barnes, K.L., Diz, D.I., Ferrario, C.M. Hypertension (1991) [Pubmed]
  7. Substance-P antagonists: effect on spontaneous and drug-induced locomotor activity in the rat. Elliott, P.J., Iversen, S.D. Neuropharmacology (1987) [Pubmed]
  8. Mnemogenic effects of injecting RA-octil, a CE-inhibitor derivate, systemically or into the basal forebrain. Gerhardt, P., Hasenöhrl, R.U., Hock, F.J., Huston, J.P. Psychopharmacology (Berl.) (1993) [Pubmed]
  9. Substance P in the descending cholinergic projection to REM sleep-induction regions of the rat pontine reticular formation: anatomical and electrophysiological analyses. Kohlmeier, K.A., Burns, J., Reiner, P.B., Semba, K. Eur. J. Neurosci. (2002) [Pubmed]
  10. Alterations of immunoreactive substance P and enkephalins in rat spinal cord after electroacupuncture. Vacca-Galloway, L.L., Naftchi, N.E., Arakawa, K., Guan, X.M., Ai, M.K. Peptides (1985) [Pubmed]
  11. Role of endogenous substance P in stress-induced activation of mesocortical dopamine neurones. Bannon, M.J., Elliott, P.J., Alpert, J.E., Goedert, M., Iversen, S.D., Iversen, L.L. Nature (1983) [Pubmed]
  12. Plasticity of substance P in mature and aged sympathetic neurons in culture. Adler, J.E., Black, I.B. Science (1984) [Pubmed]
  13. Opposing mechanisms of regulation of a G-protein-coupled inward rectifier K+ channel in rat brain neurons. Velimirovic, B.M., Koyano, K., Nakajima, S., Nakajima, Y. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  14. NK1 receptor antagonist blocks angiotensin II responses in renin transgenic rat medulla oblongata. Diz, D.I., Westwood, B., Bosch, S.M., Ganten, D., Ferrario, C. Hypertension (1998) [Pubmed]
  15. Retrograde tracing of nerve fibers to the rat middle cerebral artery with true blue: colocalization with different peptides. Edvinsson, L., Hara, H., Uddman, R. J. Cereb. Blood Flow Metab. (1989) [Pubmed]
  16. Substance P and peripheral inflammatory hyperalgesia. Nakamura-Craig, M., Smith, T.W. Pain (1989) [Pubmed]
  17. Spasmolytic polypeptide: a trefoil peptide secreted by rat gastric mucous cells. Jeffrey, G.P., Oates, P.S., Wang, T.C., Babyatsky, M.W., Brand, S.J. Gastroenterology (1994) [Pubmed]
  18. Congenital diaphragmatic hernia, tracheal occlusion, thyroid transcription factor-1, and fetal pulmonary epithelial maturation. Chapin, C.J., Ertsey, R., Yoshizawa, J., Hara, A., Sbragia, L., Greer, J.J., Kitterman, J.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  19. Effect of omeprazole-induced achlorhydria on trefoil peptide expression in the rat stomach. Kang, B., Alderman, B.M., Nicoll, A.J., Cook, G.A., Giraud, A.S. J. Gastroenterol. Hepatol. (2001) [Pubmed]
  20. The role of neurokinin 1 receptors in the maintenance of visceral hyperalgesia induced by repeated stress in rats. Bradesi, S., Kokkotou, E., Simeonidis, S., Patierno, S., Ennes, H.S., Mittal, Y., McRoberts, J.A., Ohning, G., McLean, P., Marvizon, J.C., Sternini, C., Pothoulakis, C., Mayer, E.A. Gastroenterology (2006) [Pubmed]
  21. A substance P (neurokinin-1) receptor mutant carboxyl-terminally truncated to resemble a naturally occurring receptor isoform displays enhanced responsiveness and resistance to desensitization. Li, H., Leeman, S.E., Slack, B.E., Hauser, G., Saltsman, W.S., Krause, J.E., Blusztajn, J.K., Boyd, N.D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  22. The trefoil peptides spasmolytic polypeptide and intestinal trefoil factor are major secretory products of the rat gut. Taupin, D.R., Pang, K.C., Green, S.P., Giraud, A.S. Peptides (1995) [Pubmed]
  23. Role of spasmolytic polypeptide in healing of stress-induced gastric lesions in rats. Konturek, P.C., Brzozowski, T., Konturek, S.J., Elia, G., Wright, N., Sliwowski, Z., Thim, L., Hahn, E.G. Regul. Pept. (1997) [Pubmed]
  24. Effects of neonatal capsaicin treatment in the neutrophil production, and expression of preprotachykinin-I and tachykinin receptors in the rat bone marrow. Franco-Penteado, C.F., De Souza, I.A., Lima, C.S., Teixeira, S.A., Muscara, M.N., De Nucci, G., Antunes, E. Neurosci. Lett. (2006) [Pubmed]
  25. Effect of substance P on somatostatin release from the isolated perfused rat stomach. Kwok, Y.N., McIntosh, C.H., Pederson, R.A., Brown, J.C. Gastroenterology (1985) [Pubmed]
  26. Depolarizing influences regulate preprotachykinin mRNA in sympathetic neurons. Roach, A., Adler, J.E., Black, I.B. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  27. Distribution and metabolism of intravenously administered trefoil factor 2/porcine spasmolytic polypeptide in the rat. Poulsen, S.S., Thulesen, J., Nexø, E., Thim, L. Gut (1998) [Pubmed]
  28. Effects of pancreatic spasmolytic Polypeptide (PSP) on epithelial cell function. Otto, W.R., Rao, J., Cox, H.M., Kotzian, E., Lee, C.Y., Goodlad, R.A., Lane, A., Gorman, M., Freemont, P.A., Hansen, H.F., Pappin, D., Wright, N.A. Eur. J. Biochem. (1996) [Pubmed]
  29. The production and characterization of a new monoclonal antibody to the trefoil peptide human spasmolytic polypeptide. Elia, G., Chinery, R., Hanby, A.M., Poulsom, R., Wright, N.A. Histochem. J. (1994) [Pubmed]
  30. Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Ebner, K., Rupniak, N.M., Saria, A., Singewald, N. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  31. Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: a potential component of nociception. Patte-Mensah, C., Kibaly, C., Mensah-Nyagan, A.G. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
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