Trefoil factor 3 precursor (Intestinal trefoil factor) (hITF) (Polypeptide P1.B) (hP1.B) [ITF] [TFI]

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Aging in the absence of TLR2 is associated with reduced IFN-gamma responses in the large intestine and increased severity of induced colitis.

Age-associated changes in immune function and their implications for intestinal inflammation are poorly understood. Defects in innate immunity have been shown to enhance intestinal inflammation and have been demonstrated upon aging. This study aimed to determine the consequences of aging in the presence and absence of TLR2 on intestinal inflammation. Young and aged (>60 weeks), control C57Bl/6 and TLR2-deficient (TLR2(-/-)) mice were examined. The cecum and mid-colon were analyzed for tissue damage, cytokine profiles, and trefoil factor 3 (TFF3) expression at baseline or after 5 days of treatment with dextran sodium sulfate (DSS) and 5 or 13 days recovery. Untreated, aged TLR2(-/-) mice had no significant intestinal inflammation but had reduced colonic IFN-gamma and IL-10 compared with younger mice. Aged TLR2(-/-) mice developed more severe colitis than other groups, as indicated by histological examination and overall weight loss. There were significant increases in colonic IFN-gamma following DSS treatment in young but not in aged mice. TFF3 was substantially reduced in the cecum and increased in the colon of aged but not younger TLR2(-/-) mice following DSS treatment. These results demonstrate that even upon aging, TLR2-deficient animals did not develop intestinal disease. However, they failed to respond appropriately to an inflammatory insult, and the consequences of this were most severe in aged animals. Cytokine and TFF3 changes associated with aging may contribute to more severe intestinal inflammation.

MeSH Terms

  • Aging
  • Animals
  • Cecum
  • Colitis
  • Colon
  • Dextran Sulfate
  • Genetic Predisposition to Disease
  • Interferon-gamma
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Toll-Like Receptor 2


Immunoassays of human trefoil factors 1 and 2: measured on serum from patients with inflammatory bowel disease.

The trefoil factors (TFF1-3) are cysteine-rich peptides expressed in the gastrointestinal tract where they play a critical role in mucosal protection and repair. The expression is up-regulated at sites of ulceration in various chronic inflammatory diseases. Recently, we presented an ELISA method for measurement of TFF3. The aims of the present study were to develop and evaluate ELISAs for the other two known human trefoil peptides, TFF1 and TFF2, and to carry out a cross-sectional study on serum TFF levels in patients with inflammatory bowel disease (IBD). The TFF1-ELISA was based on two polyclonal rabbit antibodies and the TFF2-ELISA on a monoclonal mouse antibody and a polyclonal rabbit antibody. RhTFF1 and 2 were employed to prepare the calibrators. TFF1-3 were assayed in serum from IBD patients (n=41) and controls (n=13). The TFF1- (TFF2-) ELISA had a detection limit of 3 pmol/L (6 pmol/L) and an analytical imprecision (CV(A)) of 7.0-8.8 for mean concentrations of 24-120 pmol/L (6.1-8.0 for mean concentrations of 17-77 pmol/L). The central reference intervals (n=300) were 140-1400 pmol/L (37-190 pmol/L). There was no variation with age and menstrual cycle. Food intake reduced concentrations of TFF1 by approximately 15%, but did not influence concentrations of TFF2. TFF1 and TFF3 were increased in serum from IBD patients. We have developed assays for measuring TFF1 and TFF2. Finding increased TFF concentrations in serum from IBD patients suggests that measurements of trefoil peptides may be of clinical relevance in IBD.

MeSH Terms

  • Adolescent
  • Adult
  • Aged
  • Aging
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Health
  • Humans
  • Immunoassay
  • Inflammatory Bowel Diseases
  • Male
  • Middle Aged
  • Mucins
  • Muscle Proteins
  • Peptides
  • Proteins
  • Sensitivity and Specificity
  • Trefoil Factor-1
  • Trefoil Factor-2
  • Trefoil Factor-3
  • Tumor Suppressor Proteins


The therapeutic effect of recombinant human trefoil factor 3 on hypoxia-induced necrotizing enterocolitis in immature rat.

Trefoil peptides are a new class of regulatory peptides involved in mucosal protection and repair in the gastrointestinal tract. Among them, trefoil factor 3 (TFF3) (intestinal trefoil factor) is known to be cytoprotective in the gut. The aim of this study was to determine the effect of recombinant human trefoil factor 3 (rhTFF3) on hypoxia-induced necrotizing enterocolitis (NEC) in immature rats. In the present study, thirty-two 1-day-old Wistar rat pups were randomly divided into four groups. Group 1 served as nonhypoxic controls. Group 2 rats were subjected to hypoxia reoxygenation (H/O) and then were returned to their mothers. Groups 3 and 4 rats were subjected to H/O, were returned to their mothers, and were treated with rhTFF3 intraperitoneally (0.5 mg) and subcutaneously (0.2 mg), respectively, for the next 3 days. All animals were killed on day 4, and intestine specimens were obtained to determine the histological changes, tissue level of interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), malondialdehyde (MDA), prostaglandin E2 (PGE2), tromboxane B2 (TXB2), and nitric oxide (NO). In addition, the effects of rhTFF3 on abundance of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) were also investigated. In neonatal NEC (group 2), necrosis of villi and crypts and, in some cases, transmural necrosis was observed under light microscopy. Tissue level of interleukin-8, tumor necrosis factor-alpha, malondialdehyde, prostaglandin E2, tromboxane B2, and nitric oxide were significantly higher than group 1. In addition, abundance of inducible nitric oxide synthase and cyclooxygenase 2 was markedly increased. In groups 3 and 4, only very slight intestinal injury was observed. The tissue level of interleukin-8, tumor necrosis factor-alpha, malondialdehyde, prostaglandin E2, tromboxane B2, and nitric oxide were significantly decreased in comparison to the group 2. Meanwhile, the abundance of inducible nitric oxide synthase and cyclooxygenase 2 was also marked decreased in comparison to group 2. The current study suggests a therapeutic role of TFF3 in an experimental model of NEC. Our findings may open a new insight into the treatment of NEC in newborns.

MeSH Terms

  • Aging
  • Animals
  • Cyclooxygenase 2
  • Enterocolitis, Necrotizing
  • Gene Expression Regulation
  • Humans
  • Hypoxia
  • Immunohistochemistry
  • Intestine, Small
  • Isoenzymes
  • Membrane Proteins
  • Mucins
  • Muscle Proteins
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Peptides
  • Prostaglandin-Endoperoxide Synthases
  • Rats
  • Trefoil Factor-3


Metaplasia of the duodenum shows a Helicobacter pylori-correlated differentiation into gastric-type protein expression.

The origin of gastric metaplasia of the duodenum (GMD) remains enigmatic. We studied expression of mucins and trefoil peptides in GMD to gain insight into its phenotype and origin. We examined duodenal tissue of 95 patients (0 to 83 years old, 26 with gastric Helicobacter pylori infection) for the presence of GMD. Expression was examined immunohistochemically of secretory mucins (MUC2, MUC5AC, MUC5B, and MUC6), trefoil peptides (TFF1, TFF2, and TFF3), and sucrase-isomaltase (SI). GMD, found in 37 patients, correlated positively to gastric H. pylori infection, age, and villus atrophy. MUC2 and TFF3, expressed in normal goblet cells, were absent from 100% and 87% of GMD, respectively. GMD ubiquitously expressed MUC5AC, whereas MUC5AC expression in adjacent goblet cells was closely correlated with the extent of GMD. TFF1, TFF2, and MUC6 were found in 84%, 92%, and 65% of GMD, respectively. MUC5B was absent from epithelium and GMD. SI, expressed by villus enterocytes, was absent from GMD. Brunner's glands ubiquitously expressed MUC5B, MUC6, and TFF2. GMD was characterized by the expression of gastric-type proteins MUC5AC, MUC6, TFF1, and TFF2 and the absence of intestinal markers MUC2, TFF3, and SI. In terms of the location of metaplastic cells, our results suggest that epithelial cells migrating toward villus tips switch to gastric-type secretory cells. Positive correlation with infection suggests an inductive role H. pylori in the development of GMD.

MeSH Terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aging
  • Brunner Glands
  • Cell Differentiation
  • Child
  • Child, Preschool
  • Duodenum
  • Gastric Mucosa
  • Goblet Cells
  • Growth Substances
  • Helicobacter Infections
  • Helicobacter pylori
  • Humans
  • Infant
  • Metaplasia
  • Middle Aged
  • Mucin 5AC
  • Mucin-2
  • Mucin-5B
  • Mucin-6
  • Mucins
  • Muscle Proteins
  • Neuropeptides
  • Peptides
  • Proteins
  • Stomach Diseases
  • Trefoil Factor-1
  • Trefoil Factor-2
  • Trefoil Factor-3
  • Tumor Suppressor Proteins