Multifactorial patterns of gene expression in colonic epithelial cells predict disease phenotypes in experimental colitis†
Aubrey L. Frantz BS
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorMaria E.C. Bruno PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorEric W. Rogier BS
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorHalide Tuna BS
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorDonald A. Cohen PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorSubbarao Bondada PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorR. Lakshman Chelvarajan PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorJ. Anthony Brandon PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorC. Darrell Jennings MD
Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorCorresponding Author
Charlotte S. Kaetzel PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky, 203 Combs Cancer Research Building, 800 Rose St., Lexington, KY 40536-0096Search for more papers by this authorAubrey L. Frantz BS
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorMaria E.C. Bruno PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorEric W. Rogier BS
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorHalide Tuna BS
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorDonald A. Cohen PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorSubbarao Bondada PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorR. Lakshman Chelvarajan PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorJ. Anthony Brandon PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorC. Darrell Jennings MD
Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky
Search for more papers by this authorCorresponding Author
Charlotte S. Kaetzel PhD
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky, 203 Combs Cancer Research Building, 800 Rose St., Lexington, KY 40536-0096Search for more papers by this authorSupported by the National Institutes of Health grants R21AI069027 (to C.S.K.) and R21AI076956 (to S.B.) and a Crohn's & Colitis Foundation of America Senior Research Award (to C.S.K.).
Abstract
Background:
The pathogenesis of inflammatory bowel disease (IBD) is complex and the need to identify molecular biomarkers is critical. Epithelial cells play a central role in maintaining intestinal homeostasis. We previously identified five “signature” biomarkers in colonic epithelial cells (CEC) that are predictive of disease phenotype in Crohn's disease. Here we investigate the ability of CEC biomarkers to define the mechanism and severity of intestinal inflammation.
Methods:
We analyzed the expression of RelA, A20, pIgR, tumor necrosis factor (TNF), and macrophage inflammatory protein (MIP)-2 in CEC of mice with dextran sodium sulfate (DSS) acute colitis or T-cell-mediated chronic colitis. Factor analysis was used to combine the five biomarkers into two multifactorial principal components (PCs). PC scores for individual mice were correlated with disease severity.
Results:
For both colitis models, PC1 was strongly weighted toward RelA, A20, and pIgR, and PC2 was strongly weighted toward TNF and MIP-2, while the contributions of other biomarkers varied depending on the etiology of inflammation. Disease severity was correlated with elevated PC2 scores in DSS colitis and reduced PC1 scores in T-cell transfer colitis. Downregulation of pIgR was a common feature observed in both colitis models and was associated with altered cellular localization of pIgR and failure to transport IgA.
Conclusions:
A multifactorial analysis of epithelial gene expression may be more informative than examining single gene responses in IBD. These results provide insight into the homeostatic and proinflammatory functions of CEC in IBD pathogenesis and suggest that biomarker analysis could be useful for evaluating therapeutic options for IBD patients. (Inflamm Bowel Dis 2012;)
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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