title: 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.
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; louise.judd@mcri.edu.au.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Judd
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: Heather V
authors.initials: HV
authors.lastname: Chalinor
authors.affiliation: RMIT University, Bundoora, Victoria, Australia; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Walduck
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Pavlic
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: Jan
authors.initials: J
authors.lastname: Däbritz
authors.affiliation: Department of Medicine and Irving Cancer Research Centre, Columbia University, New York, New York.
authors.forename: Zinaida
authors.initials: Z
authors.lastname: Dubeykovskaya
authors.affiliation: Department of Medicine and Irving Cancer Research Centre, Columbia University, New York, New York.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: Trevelyan R
authors.initials: TR
authors.lastname: Menheniott
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia;
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Giraud
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D000067596:Interleukin-33; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009077:Mucins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D010455:Peptides / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D015431:Weight Loss
chemical_list: D016207:Cytokines; C506535:Il33 protein, mouse; D018836:Inflammation Mediators; D000067596:Interleukin-33; D015850:Interleukin-6; D007378:Interleukins; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; C481546:TFF2 protein, mouse; C472724:Tff1 protein, mouse; C493263:Tff3 protein, mouse; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; C577686:interleukin-6, mouse; D016264:Dextran Sulfate
keywords: IL-33; colitis; dextran sodium sulfate; mucosal immunity; trefoil; trefoil factor 2