Cellular senescence or EGFR signaling induces Interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR)

Christoph Garbers, Fabian Kuck, Samadhi Aparicio-Siegmund, Kirstin Konzak, Mareike Kessenbrock, Annika Sommerfeld, Dieter Häussinger, Philipp A. Lang, Dirk Brenner, Tak W. Mak, Stefan Rose-John, Frank Essmann, Klaus Schulze-Osthoff, Roland P. Piekorz, Jürgen Scheller*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

51 Citations (Scopus)

Abstract

Interleukin 6 (IL-6) signaling plays a role in inflammation, cancer, and senescence. Here, we identified soluble IL-6 receptor (sIL-6R) as a member of the senescence-associated secretory phenotype (SASP). Senescence-associated sIL-6R upregulation was mediated by mammalian target of rapamycin (mTOR). sIL-6R was mainly generated by a disintegrin and metalloprotease 10 (ADAM10)-dependent ectodomain shedding to enable IL-6 trans-signaling. In vivo, heterozygous PTEN-knockout mice exhibited higher mTOR activity and increased sIL-6R levels. Moreover, aberrant EGF receptor (EGFR) activation triggered IL-6 synthesis. In analogy to senescence, EGFR-induced activation of mTOR also induced IL-6R expression and sIL-6R generation. Hence, mTOR activation reprograms IL-6 non-responder cells into IL-6 responder cells. Our data suggest that mTOR serves as a central molecular switch to facilitate cellular IL-6 classic and trans-signaling via IL-6R upregulation with direct implications for cellular senescence and tumor development.

Original languageEnglish
Pages (from-to)3421-3432
Number of pages12
JournalCell Cycle
Volume12
Issue number21
DOIs
Publication statusPublished - 1 Nov 2013
Externally publishedYes

Keywords

  • EGFR
  • Interleukin 6
  • Interleukin 6 receptor
  • SASP
  • Senescence
  • mTOR

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