title: The Src kinase Fyn is protective in acute chemical-induced colitis and promotes recovery from disease.
abstract: Despite progress in understanding enteric inflammation, current therapies, although effective in many patients with inflammatory bowel disease (IBD), have significant side-effects, and, in many patients, it is refractory to treatment. The Src kinase Fyn mediated IFN-γ-induced increased permeability in model epithelia, and so we hypothesized that inhibition of Fyn kinase would be anti-colitic. Mice [B6.129SF2/J wild-type (WT), Fyn KO, or chimeras] received 2.5% dextran sodium sulfate (DSS) or normal water for 10 d and were necropsied immediately or 3 d later. Gut permeability was assessed by FITC-dextran flux, colitis by macroscopic and histologic parameters, and immune cell status by cytokine production and CD4(+) T cell Foxp3 expression. Fyn KO mice consistently displayed significantly worse DSS-induced disease than WT, correlating with decreased IL-10 and increased IL-17 in splenocytes and the gut; Fyn KO mice failed to thrive after removal of the DSS water. Analysis of chimeric mice indicated that the increased sensitivity to DSS was due to the lack of Fyn kinase in hematopoietic, but not stromal, cells, in accordance with Fyn(+) T cell increases in WT mice exposed to DSS and Fyn KO mice having a reduced number of CD4(+)Foxp3(+) cells in baseline or colitic conditions and a reduced capacity to induce Foxp3 expression in vitro. Other experiments suggest that the colonic microbiota in Fyn KO mice is not preferentially colitogenic. Contrary to our expectation, the absence of Fyn kinase resulted in greater DSS-induced disease, and analysis of chimeric mice indicated that leukocyte Fyn kinase is beneficial in limiting colitis.
authors: *Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Department of Medicine, Department of Paediatrics, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors: Fernando
authors: F
authors: Lopes
authors: *Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Department of Medicine, Department of Paediatrics, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors: Arthur
authors: A
authors: Wang
authors: *Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Department of Medicine, Department of Paediatrics, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors: David
authors: D
authors: Smyth
authors: *Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Department of Medicine, Department of Paediatrics, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors: Jose-Luis
authors: JL
authors: Reyes
authors: *Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Department of Medicine, Department of Paediatrics, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors: Axinia
authors: A
authors: Doering
authors: *Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Department of Medicine, Department of Paediatrics, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors: L Patrick
authors: LP
authors: Schenck
authors: *Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Department of Medicine, Department of Paediatrics, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors: Paul
authors: P
authors: Beck
authors: *Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Department of Medicine, Department of Paediatrics, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada dmckay@ucalgary.ca.
authors: Christopher
authors: C
authors: Waterhouse
authors: *Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Department of Medicine, Department of Paediatrics, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada dmckay@ucalgary.ca.
authors: Derek M
authors: DM
authors: McKay
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D020381:Interleukin-17; D016753:Interleukin-10; D016264:Dextran Sulfate; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn
keywords: Foxp3; dextran sodium sulfate; inflammatory bowel disease; regulatory T cell