Interleukin-6 secretion is limited by self-signaling in endosomes

Daniëlle R J Verboogen, Natalia H Revelo, Martin Ter Beest, Geert van den Bogaart*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)
198 Downloads (Pure)

Abstract

Cells producing cytokines often express the receptor for the same cytokine, which makes them prone to autocrine signaling. How cytokine release and signaling are regulated in the same cell is not understood. In this study, we demonstrate that signaling by exogenous and self-synthesized inflammatory cytokine interleukin-6 (IL-6) within endosomal compartments acts as a cellular brake that limits synthesis of IL-6. Our data show that IL-6 is internalized by dendritic cells and signals from endosomal compartments containing the IL-6 receptor. Newly synthesized IL-6 also traffics via these endosomal compartments and signals in transit to the plasma membrane. This allows activation of STAT3 which in turn limits Toll-like receptor 4 stimulant lipopolysaccharide (LPS) triggered transcription of IL-6. Long-term exposure to LPS removes this brake via inhibition of STAT3 by increased expression of suppressor of cytokine signaling 3 (SOCS3) and results in fully-fledged IL-6 production. This transient regulation could prevent excessive IL-6 production during early infections.

Original languageEnglish
Pages (from-to)144-157
Number of pages14
JournalThe Journal of Cell Biology
Volume11
Issue number2
Early online date16-Jul-2018
DOIs
Publication statusPublished - Feb-2019

Keywords

  • membrane traffickin
  • cytokine release
  • exocytosis
  • interleukin-6
  • endosomal signaling
  • PRO-INFLAMMATORY CYTOKINES
  • BLOOD MONONUCLEAR-CELLS
  • DENDRITIC CELLS
  • RECEPTOR-ALPHA
  • HUMAN IL-6
  • MAXIMAL ACTIVATION
  • IN-VIVO
  • STAT3
  • SERUM
  • GP130

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