Multi-scale in vivo systems analysis reveals the influence of immune cells on TNF-α-induced apoptosis in the intestinal epithelium.

Lau KS, Cortez-Retamozo V, Philips SR, Pittet MJ, Lauffenburger DA, Haigis KM
PLoS Biol. 2012 10 (9): e1001393

PMID: 23055830 · PMCID: PMC3463506 · DOI:10.1371/journal.pbio.1001393

Intestinal epithelial cells exist within a complex environment that affects how they interpret and respond to stimuli. We have applied a multi-scale in vivo systems approach to understand how intestinal immune cells communicate with epithelial cells to regulate responses to inflammatory signals. Multivariate modeling analysis of a large dataset composed of phospho-signals, cytokines, and immune cell populations within the intestine revealed an intimate relationship between immune cells and the epithelial response to TNF-α. Ablation of lymphocytes in the intestine prompted a decrease in the expression of MCP-1, which in turn increased the steady state number of intestinal plasmacytoid dendritic cells (pDCs). This change in the immune compartment affected the intestinal cytokine milieu and subsequent epithelial cell signaling network, with cells becoming hypersensitive to TNF-α-induced apoptosis in a way that could be predicted by mathematical modeling. In summary, we have uncovered a novel cellular network that regulates the response of intestinal epithelial cells to inflammatory stimuli in an in vivo setting.

MeSH Terms (16)

Animals Apoptosis Cell Movement Chemokine CCL2 Dendritic Cells Epithelial Cells Interferon-gamma Intestinal Mucosa Lymphocytes Mice Mice, Inbred C57BL Models, Biological Neutralization Tests Phenotype Signal Transduction Tumor Necrosis Factor-alpha

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