title: Epithelial tyrosine phosphatase SHP-2 protects against intestinal inflammation in mice.
abstract: Polymorphisms of PTPN11 encoding SHP-2 are biomarkers for ulcerative colitis (UC) susceptibility. However, their functional relevance is unknown. We thus investigated the role of epithelial SHP-2 in the control of intestinal homeostasis. Mice with an intestinal epithelial cell-specific SHP-2 deletion (SHP-2(IEC-KO) mice) were generated. Control and SHP-2(IEC-KO) mice were monitored for clinical symptoms and sacrificed for histological staining and Western blot analyses. Cytokines and chemokines, as well as intestinal permeability, were quantified. SHP-2 mRNA expression was evaluated in control and UC patients. SHP-2(IEC-KO) mice showed growth retardation compared to control littermates and rapidly developed severe colitis. Colon architecture was markedly altered with infiltration of immune cells, crypt abscesses, neutrophil accumulation, and reduced goblet cell numbers. Decreased expression of claudins was associated with enhanced intestinal permeability in mutant SHP-2(IEC-KO) mice. Inflammatory transcription factors Stat3 and NF-κB were hyperactivated early in the mutant colonic epithelium. Levels of several epithelial chemokines and cytokines were markedly enhanced in SHP-2(IEC-KO) mice. Of note, antibiotic treatment remarkably impaired the development of colitis in SHP-2(IEC-KO) mice. Finally, SHP-2 mRNA levels were significantly reduced in intestinal biopsy specimens from UC patients. Our results establish intestinal epithelial SHP-2 as a critical determinant for prevention of gut inflammation.
authors.affiliation: Département d'Anatomie et de Biologie Cellulaire, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Coulombe
authors.forename: Caroline
authors.initials: C
authors.lastname: Leblanc
authors.forename: Sébastien
authors.initials: S
authors.lastname: Cagnol
authors.forename: Faiza
authors.initials: F
authors.lastname: Maloum
authors.forename: Etienne
authors.initials: E
authors.lastname: Lemieux
authors.forename: Nathalie
authors.initials: N
authors.lastname: Perreault
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: François
authors.initials: F
authors.lastname: Boudreau
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rivard
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D003092:Colitis / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D003093:Colitis, Ulcerative / Q000201:enzymology* / Q000235:genetics; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010539:Permeability; D011247:Pregnancy; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11