TFF2 deficiency exacerbates weight loss and alters immune cell and cytokine profiles in DSS colitis, and this cannot be rescued by wild-type bone marrow

Abstract

The trefoil factor TFF2 is a member of a tripartite family of small proteins that is produced by the stomach and the colon. Recombinant TFF2, when applied intrarectally in a rodent model of hapten colitis, hastens mucosal healing and reduces inflammatory indexes. Additionally, TFF2 is expressed in immune organs, supporting a potential immunomodulatory and reparative role in the bowel. In this study we confirm that TFF2 is expressed in the colon and is specifically enriched in epithelial cells relative to colonic leukocytes. TFF2-deficient, but not TFF1-deficient, mice exhibit a more severe response to acute or chronic dextran sulfate (DSS)-induced colitis that correlates with a 50% loss of expression of TFF3, the principal colonic trefoil. In addition, the response to acute colitis is associated with altered expression of IL-6 and IL-33, but not other inflammatory cytokines. While TFF2 can reduce macrophage responsiveness and block inflammatory cell recruitment to the colon, the major role in limiting the susceptibility to acute colitis appears to be maintenance of barrier function. Bone marrow transfer experiments demonstrate that leukocyte expression of TFF2 is not sufficient for prevention of colitis induction but, rather, that the gastrointestinal epithelium is the primary source of TFF2. Together, these findings illustrate that epithelial TFF2 is an important endogenous regulator of gut mucosal homeostasis that can modulate immune and epithelial compartments. Because of its extreme stability, even in the corrosive gut lumen, TFF2 is an attractive candidate as an oral therapeutic scaffold for future drug development in the treatment of inflammatory bowel disease.

Trefoil Factor Peptides and Gastrointestinal Function

“…TFF2 reduces colonic inflammation by inhibiting NO production derived from iNOS in monocytes (148). Following DSS-induced colitis, Tff2 KO mice, but not Tff1 KO mice, show severe weight loss accompanied with an altered inflammatory cytokine expression profile, such as further upregulation of Il-6 and downregulation of Il-33, when compared with WT mice (149). Interestingly, the peritoneal macrophages from Tff2 KO mice show downregulation of Il-6 , Il-1β , Il-10 , Il-19 , and Il-33 compared to WT mice.…”

“…Interestingly, the peritoneal macrophages from Tff2 KO mice show downregulation of Il-6 , Il-1β , Il-10 , Il-19 , and Il-33 compared to WT mice. Additionally, LPS stimulation enhanced an increase of Il-6 and Il-1β production and reduced levels of Il-10 and Il-19 production, whereas Il-33 sustained a low level in the peritoneal macrophages from Tff2 KO mice (149). As TFF3 expression is altered in the Tff2 KO mice, it is possible that some of these effects are mediated by TFF3.…”

Involvement of trefoil factor family 2 in the enlargement of intestinal tumors in ApcMin/+ mice

“…2B). Although, a possibility that immune modulation by Tff2 would participate on tumor development as reported [19], Tff2, at last, could enlarge tumor size independently from immune response, because the xenograft experiment in our present study used nude mice which deficient in immune system (Fig. 2C).…”

Zeolite-Containing Mixture Supplementation Ameliorated Dextran Sodium Sulfate-Induced Colitis in Mice by Suppressing the Inflammatory Bowel Disease Pathway and Improving Apoptosis in Colon Mucosa

“…The above-described findings might be supported by the colon histology results showing that the status of the goblet cells damaged by DSS was alleviated in the DHY8 mice compared to the DSS mice. In addition, TFF2 deficiency has been reported to lead to a loss of body weight [33], and the upregulation of TFF2 induced by HY supplementation seems consistent with improved body weight loss.…”

“…The downregulation of Egfr by HY supplementation indicates the improvement of colitic status. Tff2 , which is secreted and expressed by gastrointestinal epithelium and plays a vital role in the maintenance of epithelial integrity and mucosal surfaces [33], was upregulated by HY supplementation. Moreover, Tff2 is essential in the immune response in inflammatory conditions by controlling the expression of pro-inflammatory cytokines such as IL6 and IL1β [34].…”