Research ArticleSystems Biology

In Vivo Systems Analysis Identifies Spatial and Temporal Aspects of the Modulation of TNF-α–Induced Apoptosis and Proliferation by MAPKs

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Science Signaling  22 Mar 2011:
Vol. 4, Issue 165, pp. ra16
DOI: 10.1126/scisignal.2001338

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Gut Feelings

Chronic gut inflammation can lead to inflammatory bowel disease (IBD), a debilitating condition in which normal intestinal epithelial homeostasis is disrupted. The inflammatory cytokine tumor necrosis factor–α (TNF-α), which is implicated in IBD, triggers both pro-apoptotic and pro-survival responses in cells. Lau et al. performed a systems-based analysis of the effects of systemic TNF-α in the mouse small intestine. Even within this small area, TNF-α–dependent effects varied in their timing and location, with apoptosis triggered in the duodenum and proliferation in the ileum. Analysis of the extent of protein phosphorylation together with modeling predicted that the extracellular signal–regulated kinase (ERK) pathway was critical in mediating responses to TNF-α. Indeed, pharmacological inhibition of ERK signaling in TNF-α–treated mice differentially affected TNF-α–induced responses. This study demonstrates that analysis of signaling at the systems level can be used to depict apoptotic and proliferative responses in vivo and to generate testable hypotheses and identify potential therapeutic targets from model predictions.

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