Interleukin-6 secretion is limited by self-signaling in endosomes. (16th July 2018)

• Record Type: Journal Article
• Authors: Verboogen, Daniëlle R J; Revelo, Natalia H; ter Beest, Martin; van den Bogaart, Geert
• Editors: Su, Bing
• Is Part Of: Journal of molecular cell biology. Volume 11:Number 2(2019)
• Page Start: 144
• Page End: 157
• Publication Date: 2018-07-16
• Subjects: membrane trafficking -- cytokine release -- exocytosis -- interleukin-6 -- endosomal signaling; Molecular biology -- Periodicals; 571.605
• DOI: 10.1093/jmcb/mjy038
• Languages: English
• ISSNs: 1674-2788

Abstract

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 the 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 and results in fully fledged IL-6 production. This transient regulation could prevent excessive IL-6 production during early infections.