Trefoil Family Factor 2 Is Expressed in Murine Gastric and Immune Cells and Controls both Gastrointestinal Inflammation and Systemic Immune Responses

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.

Loss of Trefoil Factor 2 From Pancreatic Duct Glands Promotes Formation of Intraductal Papillary Mucinous Neoplasms in Mice

“…TFF2 is uniquely expressed in PDG and has been shown to possess tumor suppressor-like qualities in gastric cancer 30 . To explore the hypothesis that TFF2 functions as a tumor suppressor in PDG, we employed a genetically engineered mouse model of pancreatic cancer with TFF2 deficiency (KC/TFF2−/−).…”

Porcine Gastric TFF2 is a Mucus Constituent and Differs from Pancreatic TFF2

“…In line with this hypothesis, TFF2 applied luminally to the gastric mucosa inhibited H + permeation through the mucus barrier [29] and Tff2-deficient mice (Tff2 KO ) have induced susceptibility to Helicobacter -induced gastritis [30], they showed accelerated progression to dysplasia [31], and their gastric surface pH was attenuated after photodamage [32]. Thus far, the interaction partners of TFF2 and the type of interaction are not known.…”

“…TFF2 is also expressed in the brain and pituitary [33] as well as in immune cells such as macrophages and lymphocytes [30,34]. Tff2 KO mice show an altered expression of genes implicated in immune regulation [35] and their immune cells are hyperresponsive to IL-1β stimulation [30].…”

“…Tff2 KO mice show an altered expression of genes implicated in immune regulation [35] and their immune cells are hyperresponsive to IL-1β stimulation [30]. …”

Trefoil Factor Peptides and Gastrointestinal Function

“…In Tff2 KO mice, exogenous TFF3 can inhibit gastric injury induced by indomethacin or ethanol in rats (49) and rescue the delayed gastric epithelial repair in these mutant mice lacking Tff2 (27). Tff2 KO mice also show an increased susceptibility to DSS-induced colonic injury (57). …”