Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Selvi Ramasamy, Borja Saez, Subhankar Mukhopadhyay, Daching Ding, Alwiya M. Ahmed, Xi Chen, Ferdinando Pucci, Rae'e Yamin, Jianfeng Wang, Mikael J. Pittet, Cassandra M. Kelleher, David T. Scadden, David A. Sweetser

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1Δ/Δ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.

Original languageEnglish (US)
Pages (from-to)1871-1876
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number7
DOIs
StatePublished - Feb 16 2016

Keywords

  • HES1
  • Inflammation
  • NF-κB
  • TLE1
  • Tumor suppressor

ASJC Scopus subject areas

  • General

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    Ramasamy, S., Saez, B., Mukhopadhyay, S., Ding, D., Ahmed, A. M., Chen, X., Pucci, F., Yamin, R., Wang, J., Pittet, M. J., Kelleher, C. M., Scadden, D. T., & Sweetser, D. A. (2016). Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway. Proceedings of the National Academy of Sciences of the United States of America, 113(7), 1871-1876. https://doi.org/10.1073/pnas.1511380113