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

Journal of Molecular Cell Biology
Daniëlle R J VerboogenGeert van den Bogaart

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.

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Citations

Aug 3, 2019·Experimental Dermatology·Giorgio ManginoGiovanna Romeo
Sep 29, 2020·Frontiers in Immunology·Alexandra BirzerLinda Popella
Oct 12, 2019·Journal of Cell Science·Natalia H ReveloGeert van den Bogaart
Nov 15, 2018·International Journal of Molecular Sciences·Masashi Narazaki, Tadamitsu Kishimoto
Dec 31, 2020·International Journal of Molecular Sciences·Alexandra DamerauAnnemarie Lang
Jun 12, 2021·Journal of Leukocyte Biology·Arvin Tejnarine PersaudChristina Guzzo
Jul 7, 2021·Biochemistry. Biokhimii︠a︡·Alexey A KvichanskyNatalia V Gulyaeva
Jun 19, 2021·Frontiers in Cell and Developmental Biology·Dirk Schmidt-Arras, Stefan Rose-John
Aug 11, 2021·Journal of Translational Medicine·Bangbao TaoJun Zhong
Aug 19, 2021·Journal of Leukocyte Biology·Yu-Dong XuYong-Qing Yang
Jun 11, 2021·Clinical and Experimental Immunology·Yanfang ZhaoYuekang Xu

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Datasets Mentioned

BETA
GM-CSF

Methods Mentioned

BETA
flow cytometry
ELISA
glycosylation
Transmission electron microscopy
confocal microscopy
Fluorescence microscopy

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