Trp53 deficiency protects against acute intestinal inflammation

Martina E. Spehlmann, Carolin F. Manthey, Sara Dann-Grice, 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

Research output: Contribution to journalArticle

22 Citations (Scopus)

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

Fingerprint

Interleukin-6
Inflammation
Epithelial Cells
NF-kappa B
Colitis
Neoplasms
Mucous Membrane
Phosphotransferases
Epithelium
Macrophages
Glucose
Proteins
Protective Factors

ASJC Scopus subject areas

  • Immunology

Cite this

Spehlmann, M. E., Manthey, C. F., Dann-Grice, S., Hanson, E., Sandhu, S. S., Liu, L. Y., ... Eckmann, L. (2013). Trp53 deficiency protects against acute intestinal inflammation. Journal of Immunology, 191(2), 837-847. https://doi.org/10.4049/jimmunol.1201716

Trp53 deficiency protects against acute intestinal inflammation. / Spehlmann, Martina E.; Manthey, Carolin F.; Dann-Grice, Sara; Hanson, Elaine; Sandhu, Sukhman S.; Liu, Linus Y.; Abdelmalak, Farid K.; Diamanti, Michaela A.; Retzlaff, Kristin; Scheller, Jürgen; Rose-John, Stefan; Greten, Florian R.; Wang, Jean Y J; Eckmann, Lars.

In: Journal of Immunology, Vol. 191, No. 2, 15.07.2013, p. 837-847.

Research output: Contribution to journalArticle

Spehlmann, ME, Manthey, CF, Dann-Grice, S, Hanson, E, Sandhu, SS, Liu, LY, Abdelmalak, FK, Diamanti, MA, Retzlaff, K, Scheller, J, Rose-John, S, Greten, FR, Wang, JYJ & Eckmann, L 2013, 'Trp53 deficiency protects against acute intestinal inflammation', Journal of Immunology, vol. 191, no. 2, pp. 837-847. https://doi.org/10.4049/jimmunol.1201716
Spehlmann ME, Manthey CF, Dann-Grice S, Hanson E, Sandhu SS, Liu LY et al. Trp53 deficiency protects against acute intestinal inflammation. Journal of Immunology. 2013 Jul 15;191(2):837-847. https://doi.org/10.4049/jimmunol.1201716
Spehlmann, Martina E. ; Manthey, Carolin F. ; Dann-Grice, Sara ; Hanson, Elaine ; Sandhu, Sukhman S. ; Liu, Linus Y. ; Abdelmalak, Farid K. ; Diamanti, Michaela A. ; Retzlaff, Kristin ; Scheller, Jürgen ; Rose-John, Stefan ; Greten, Florian R. ; Wang, Jean Y J ; Eckmann, Lars. / Trp53 deficiency protects against acute intestinal inflammation. In: Journal of Immunology. 2013 ; Vol. 191, No. 2. pp. 837-847.
@article{0c1544a6284c4eef9fbfdf65a1da0abf,
title = "Trp53 deficiency protects against acute intestinal inflammation",
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.",
author = "Spehlmann, {Martina E.} and Manthey, {Carolin F.} and Sara Dann-Grice and Elaine Hanson and Sandhu, {Sukhman S.} and Liu, {Linus Y.} and Abdelmalak, {Farid K.} and Diamanti, {Michaela A.} and Kristin Retzlaff and J{\"u}rgen Scheller and Stefan Rose-John and Greten, {Florian R.} and Wang, {Jean Y J} and Lars Eckmann",
year = "2013",
month = "7",
day = "15",
doi = "10.4049/jimmunol.1201716",
language = "English (US)",
volume = "191",
pages = "837--847",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "2",

}

TY - JOUR

T1 - Trp53 deficiency protects against acute intestinal inflammation

AU - Spehlmann, Martina E.

AU - Manthey, Carolin F.

AU - Dann-Grice, Sara

AU - Hanson, Elaine

AU - Sandhu, Sukhman S.

AU - Liu, Linus Y.

AU - Abdelmalak, Farid K.

AU - Diamanti, Michaela A.

AU - Retzlaff, Kristin

AU - Scheller, Jürgen

AU - Rose-John, Stefan

AU - Greten, Florian R.

AU - Wang, Jean Y J

AU - Eckmann, Lars

PY - 2013/7/15

Y1 - 2013/7/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84880085172&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880085172&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1201716

DO - 10.4049/jimmunol.1201716

M3 - Article

VL - 191

SP - 837

EP - 847

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 2

ER -