title: Endogenous prion protein attenuates experimentally induced colitis.
abstract: Although the cellular prion protein (PrP(C)) is expressed in the enteric nervous system and lamina propria, its function(s) in the gut is unknown. Because PrP(C) may exert a cytoprotective effect in response to various physiologic stressors, we hypothesized that PrP(C) expression levels might modulate the severity of experimental colitis. We evaluated the course of dextran sodium sulfate (DSS)-induced colitis in hemizygous Tga20 transgenic mice (approximately sevenfold overexpression of PrP(C)), Prnp(-/-) mice, and wild-type mice. On day 7, colon length, disease severity, and histologic activity indices were determined. Unlike DSS-treated wild-type and Prnp(-/-) animals, PrP(C) overexpressing mice were resistant to colitis induction, exhibited much milder histopathologic features, and did not exhibit weight loss or colonic shortening. In keeping with these results, pro-survival molecule expression and/or phosphorylation levels were elevated in DSS-treated Tga20 mice, whereas pro-inflammatory cytokine production and pSTAT3 levels were reduced. In contrast, DSS-treated Prnp(-/-) mice exhibited increased BAD protein expression and a cytokine expression profile predicted to favor inflammation and differentiation. PrP(C) expression from both the endogenous Prnp locus or the Tga20 transgene was increased in the colons of DSS-treated mice. Considered together, these findings demonstrate that PrP(C) has a previously unrecognized cytoprotective and/or anti-inflammatory function within the murine colon.
authors.affiliation: Department of Biochemistry and Molecular Biology and the McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Martin
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Keenan
authors.forename: Keith A
authors.initials: KA
authors.lastname: Sharkey
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jirik
mesh_terms: D000818:Animals; D017209:Apoptosis; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004198:Disease Susceptibility; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010539:Permeability; D011328:Prions / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015431:Weight Loss / Q000502:physiology; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: C494820:Bad protein, mouse; D016207:Cytokines; D011328:Prions; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051025:bcl-Associated Death Protein; D016264:Dextran Sulfate