Trp53 deficiency protects against acute intestinal inflammation

Martina E. Spehlmann, Carolin F. Manthey, Sara M. Dann, Elaine Hanson, Sukhman S. Sandhu, Linus Y. Liu, Farid K. Abdelmalak, Michaela A. Diamanti, Kristin Retzlaff, Jürgen Scheller, Stefan Rose-John, Florian R. Greten, Jean Y.J. Wang, Lars Eckmann

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25 Scopus citations

Abstract

The p53 protein has not only important tumor suppressor activity but also additional immunological and other functions, whose nature and extent are just beginning to be recognized. In this article, we show that p53 has a novel inflammation-promoting action in the intestinal tract, because loss of p53 or the upstream activating kinase, ATM, protects against acute intestinal inflammation in murine models. Mechanistically, deficiency in p53 leads to increased survival of epithelial cells and lamina propria macrophages, higher IL-6 expression owing to enhanced glucose-dependent NF-kB activation, and increased mucosal STAT3 activation. Blockade or loss of IL-6 signaling reverses the protective effects of p53 deficiency. Conversely, IL-6 treatment protects against acute colitis in a manner dependent on STAT3 signaling and induction of cytoprotective factors in epithelial cells. Together, these results indicate that p53 promotes inflammation in the intestinal tract through suppression of epithelium-protective factors, thus significantly expanding the spectrum of physiological and immunological p53 activities unrelated to cancer formation.

Original languageEnglish (US)
Pages (from-to)837-847
Number of pages11
JournalJournal of Immunology
Volume191
Issue number2
DOIs
StatePublished - Jul 15 2013

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Spehlmann, M. E., Manthey, C. F., Dann, S. M., Hanson, E., Sandhu, S. S., Liu, L. Y., Abdelmalak, F. K., Diamanti, M. A., Retzlaff, K., Scheller, J., Rose-John, S., Greten, F. R., Wang, J. Y. J., & Eckmann, L. (2013). Trp53 deficiency protects against acute intestinal inflammation. Journal of Immunology, 191(2), 837-847. https://doi.org/10.4049/jimmunol.1201716