Trefoil Factor Family (TFF) Peptides and Their Links to Inflammation: A Re-evaluation and New Medical Perspectives

Abstract

Trefoil factor family peptides (TFF1, TFF2, TFF3), together with mucins, are typical exocrine products of mucous epithelia. Here, they act as a gastric tumor suppressor (TFF1) or they play different roles in mucosal innate immune defense (TFF2, TFF3). Minute amounts are also secreted as endocrine, e.g., by the immune and central nervous systems. As a hallmark, TFF peptides have different lectin activities, best characterized for TFF2, but also TFF1. Pathologically, ectopic expression occurs during inflammation and in various tumors. In this review, the role of TFF peptides during inflammation is discussed on two levels. On the one hand, the expression of TFF1-3 is regulated by inflammatory signals in different ways (upstream links). On the other hand, TFF peptides influence inflammatory processes (downstream links). The latter are recognized best in various Tff-deficient mice, which have completely different phenotypes. In particular, TFF2 is secreted by myeloid cells (e.g., macrophages) and lymphocytes (e.g., memory T cells), where it modulates immune reactions triggering inflammation. As a new concept, in addition to lectin-triggered activation, a hypothetical lectin-triggered inhibition of glycosylated transmembrane receptors by TFF peptides is discussed. Thus, TFFs are promising players in the field of glycoimmunology, such as galectins and C-type lectins.

Trefoil Factor Family (TFF) Peptides

“…Tiny amounts of TFF peptides also undergo endocrine secretion (for reviews, see [12,13]), such as in lymphoid organs and tissues (thymus, bone marrow, spleen, lymph nodes, gut-associated lymphatic tissue, etc. [42][43][44]), the brain [45], the thyroid, the pancreas, and probably also blood vessels.…”

“…Based upon histopathological evaluation (immunofluorescence, immunohistochemistry, in situ hybridization), the ectopic expression of TFF peptides was detected in patholog-ical conditions, particularly during chronic inflammation (for reviews, see [7,10,13,14,21]). Typical examples are gastro-esophageal reflux disease, Barrett's esophagus, gastric and duodenal ulcers, diverticulitis, inflammatory bowel disease, pancreatitis, hepatolithiasis, cholecystitis, salpingitis, inflammatory nasal polypi, and chronic obstructive lung disease (COPD).…”

“…Numerous studies have analyzed the regulation of TFF expression during inflammation in particular, and the three TFF genes have been shown to often respond differently to inflammatory mediators (for review, see [13]). Generally, the links between TFF peptides and inflammation are rather complex.…”

“…All three TFF peptides are sugar-binding proteins, i.e., they have lectin activities [58], but to different extents and with different specificities (for reviews, see [13,14]). Dimeric TFF1 binds to the core oligosaccharide of the Helicobacter pylori lipopolysaccharide, while TFF3 binds with lesser affinity [59,60].…”

“…Members of the trefoil factor family, i.e., mammalian TFF1, TFF2, and TFF3, are primarily considered secretory peptides involved in mucosal protection and defense (reviews: [1][2][3][4][5][6][7][8][9][10][11][12][13][14]). Furthermore, they are synthesized in the immune and nervous systems, and probably also blood vessels.…”