Article

Trefoil family factor 2 is expressed in murine gastric and immune cells and controls both gastrointestinal inflammation and systemic immune responses

Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Lazare Research Building Rm. 226, Worcester, MA 01605, USA.
Infection and Immunity (Impact Factor: 4.16). 02/2007; 75(1):471-80. DOI: 10.1128/IAI.02039-05
Source: PubMed

ABSTRACT Trefoil family factor 2 (TFF2), also known as spasmolytic peptide, is a low-molecular-weight protein that is upregulated in gastric tissues infected with Helicobacter or having other inflammatory conditions, but a precise function is yet to be elucidated. The role of TFF2 in the development of gastritis, colitis, and inflammatory cytokine responses was examined both in vivo and in vitro using wild-type and TFF2 knockout mice. TFF2 knockout and wild-type mice were infected with Helicobacter felis (H. felis) to induce gastritis. Colitis was induced in TFF2 knockout and wild-type mice by administering dextran sodium sulfate (DSS) in drinking water. Histopathology, clinical disease (colitis), and antibody levels (H. felis) were examined. TFF2 expression in tissues was determined by reverse transcriptase PCR, and the inflammatory and proliferative responses of TFF2-expressing macrophages and spleen cells were examined by cytokine enzyme-linked immunosorbent assay, thymidine incorporation, and gene array studies. TFF2 knockout mice have increased susceptibility to H. felis-induced gastritis, with enhanced gastric inflammation. They were also more susceptible to DSS-induced colitis, with prolonged colonic hemorrhage and persistent weight loss. Remarkably, TFF2 expression was not limited to the gastrointestinal tract, as suggested in previous studies, but was also present in macrophages and lymphocytes. The inflammatory and proliferative responses of these immune cell types were dysregulated in TFF2 knockout mice. TFF2-/- cells were hyperresponsive to interleukin 1 beta stimulation but showed normal responses to lipopolysaccharide, suggesting a specific role for TFF2 in interleukin 1 receptor but not Toll-like receptor 4 signaling via their Toll-interleukin 1 resistance domains. TFF2-/- lymphocytes also produced higher levels of interleukin 2 than wild-type cells. Thus, TFF2 was expressed in the gastrointestinal cells and in immune cells and was a negative regulator of gastrointestinal inflammation and immune cell cytokine responses. Our studies suggest that TFF2 not only controls gastrointestinal repair but also regulates mononuclear cell inflammatory responses.

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    • "ne stomach (Thim and Mortz 2000) and CXCR4 has been reported to be a low-affinity receptor for TFF2 (Dubeykovskaya et al. 2009; for review, see Hoffmann 2009). TFF2 is also expressed in immune cells and participates in immune responses and inflammatory processes, which are dysregulated in Tff2-deficient mice (Baus-Loncar et al. 2005; Kurt-Jones et al. 2007). The reference interval of TFF2 in human serum has been reported to as 37–190 pmol/L (Vestergaard et al. 2004)."
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    ABSTRACT: In the human stomach, the peptide TFF2 is secreted together with the mucin MUC6 by mucous neck cells and antral gland cells. TFF2 is strongly associated with the gastric mucus and promotes gastric restitution. Here, TFF2 was purified from the human corpus and antrum, respectively, by size exclusion chromatography, and the N-linked glycan structure at N-15 of the mature peptide determined. As a hallmark, the unusual monofucosylated N,N'-diacetylhexosediamine (tentatively assigned as GalNAcβ1→4GlcNAc, LacdiNAc) modification was detected as the terminal structure of a bi-antennary complex type N-glycan exhibiting also core fucosylation. Replicate analyses did not show microheterogeneities in the fraction of PNGaseF cleaved and permethylated N-glycans when analyzed by MALDI-mass spectrometry. On the glycopeptide level a minor glycan microheterogeneity was evident in liquid chromatography-ESI-mass spectrometry demonstrating the presence of underfucosylated species. The tryptic TFF2 N-glycopeptide p34-39 (LSPHNR N-glycosylated with Fuc3Hex3HexNAc6) was identified both by ESI-MS/MS and MALDI-post-source decay analysis. Lectin analyses with the Wisteria floribunda agglutinin indicated the potential presence of LacdiNAc terminating glycans and revealed minor differences between TFF2 from fundic units, i. e., mucous neck cells, and antral units, i. e. antral gland cells. Strikingly, on the level of the primary structure there was no indication that formation of the proposed LacdiNAc structure is cis-controled by a peptidic determinant related to published sequences.
    Glycobiology 09/2012; DOI:10.1093/glycob/cws131 · 3.14 Impact Factor
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    • "ve gastric mucus layer. Previous studies concentrated on the expression of TFFs, specifically tff1 and tff2, in the mouse model. Spasmolytic polypeptide (TFF2)-expressing metaplasia (SPEM) is observed in mucosa adjacent to human gastric cancer and in fundic glands showing oxyntic atrophy in H. felis–infected mice (Nomura et al. 2004; Kurt-Jones et al. 2007). However, there has been no comprehensive analysis of all the murine mucins and TFFs over the course of the disease. We studied the alterations in gastric mucins and TFFs as the murine disease progresses from gastritis through dysplasia and metaplasia to gastric carcinoma by both IHC and RNA expression."
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    ABSTRACT: The C57BL/6 mouse has been shown to develop gastric adenocarcinoma after Helicobacter felis infection. This model was used to determine whether mucin and trefoil factor (TFF) expression after infection was altered in a similar fashion to the changes seen in the protective gastric mucus layer of the human stomach after H. pylori infection. Our results indicate that this mouse model mimics many of the changes seen after human H. pylori infection, including increased expression of muc4 and muc5b and loss of muc5ac. These alterations in mucin expression occurred as early as 4 weeks postinfection, before the development of significant mucous metaplasia or gastric dysplasia. The decrease in muc5ac expression occurred only in the body of the stomach and was not secondary to the adaptive immune response to infection, because a similar decrease in expression was seen after infection of B6.Rag-1(-/-) mice, which lack B and T cells. Intriguingly, the increased expression of Muc4 and Muc5b in infected C57BL/6 mice was not seen in the infected B6.Rag-1(-/-) mice. Because B6.Rag-1(-/-) mice do not develop gastric pathology after H. felis infection, these findings point to the potential role of Muc4 and Muc5b in disease progression. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
    Journal of Histochemistry and Cytochemistry 02/2009; 57(5):457-67. DOI:10.1369/jhc.2009.952473 · 2.40 Impact Factor
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    ABSTRACT: AIM: To investigate the protein expression of the trefoil factor family 2 (TFF2) in fundic glands with Helicobacter pylori infection. METHODS: Protein expression of TFF2 was detected by immunohistochemistry in paraffin- embedded samples from 29 (92 blocks) surgical specimens from five patients gastric ulcer and 24 with gastric carcinoma. RESULTS: Expression of TFF2 was found in mucous neck cells and cells with pseudopylori gland metaplasia. Positive cells were distributed above the 1/2 to 2/3 portions of fundic glands in normal gastric mucosa. The ratio of TFF2- positive cells in the basal portion of the fundic glands was 18.0, 42.9 and 90.5% in mild, moder- ate and severe glandular atrophy, respectively, and these differences were significant ( P < 0.01). CONCLUSION: H pylori infection increases the expression of TFF2 in deeper parts of the fundic gland, and is also associated with the degree of glandular atrophy. The expression of TFF2 is re- lated to mucosal protection and repair processes.
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