Temporal Genome Expression Profile Analysis During T-cell-Mediated Colitis: Identification of Novel Targets and Pathways

Abstract

T cells critically regulate inflammatory bowel disease (IBD), with T-cell-dependent experimental colitis models gaining favor in identifying potential pathogenic mechanisms; yet limited understanding of specific pathogenic molecules or pathways still exists. In this study we sought to identify changes in whole genome expression profiles using the CD4CD45Rbhi T-cell transfer colitis model compared to genome expression differences from Crohn's disease (CD) tissue specimens. Colon tissue was used for histopathological and genome expression profiling analysis at 0, 2, 4, or 6 weeks after adoptive T-cell transfer. We identified 1775 genes that were significantly altered during disease progression, with 361 being progressively downregulated and 341 progressively upregulated. Gene expression changes were validated by quantitative real-time polymerase chain reaction (qRT-PCR), confirming genome expression analysis data. Differentially expressed genes were clearly related to inflammation/immune responses but also strongly associated with metabolic, chemokine signaling, Jak-STAT signaling, and angiogenesis pathways. Ingenuity network analysis revealed 25 unique network associations that were associated with functions such as antigen presentation, cell morphology, cell-to-cell signaling and interaction, as well as nervous system development and function. Moreover, many of these genes and pathways were similarly identified in CD specimens. These findings reveal novel, complex, and dynamic changes in gene expression that may provide useful targets for future therapeutic approaches.