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Oncostatin M–induced blood‐brain barrier impairment is due to prolonged activation of STAT3 signaling in vitro
Author(s) -
Takata Fuyuko,
Dohgu Shinya,
Matsumoto Junichi,
Machida Takashi,
Sakaguchi Shinya,
Kimura Ikuya,
Yamauchi Atsushi,
Kataoka Yasufumi
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.27162
Subject(s) - oncostatin m , stat3 , stat protein , phosphorylation , leukemia inhibitory factor , signal transduction , janus kinase , cytokine , microbiology and biotechnology , jak stat signaling pathway , blood–brain barrier , chemistry , medicine , endocrinology , cancer research , biology , interleukin 6 , tyrosine kinase , central nervous system
Oncostatin M (OSM) is a member of the interleukin (IL)‐6 family cytokines. We previously demonstrated that OSM induces blood‐brain barrier (BBB) impairment. However, functional characterization of IL‐6 family cytokines in BBB regulation and the cytokine‐related intracellular signaling pathway remain unclear. In this study, we demonstrate that among IL‐6 family cytokines, including IL‐6 and leukemia inhibitory factor (LIF), OSM is the most potent molecule for inducing BBB dysfunction via prolonged activation of signal transducer and activator of transcription (STAT) 3 following Janus‐activated kinase (JAK) activation. OSM but not IL‐6 and LIF (100 ng/mL for 24 hours) markedly produced increased sodium fluorescein permeability and decreased transendothelial electrical resistance in rat brain endothelial cell (RBEC) monolayers. This OSM‐induced BBB dysfunction was accompanied by decreased levels of claudin‐5 expression in RBECs, which were ameliorated by JAK inhibitor. We examined the time‐course of STAT3 phosphorylation in RBECs treated with OSM, IL‐6, and LIF. OSM upregulated STAT3 phosphorylation levels during a 24 hours period with a peak at 10 minutes. While IL‐6 and LIF transiently increased phosphorylated STAT3 at 10 minutes after addition, this phosphorylation decreased during the period from 1 to 24 hours after addition. These findings suggest that OSM‐induced sustained increases in STAT3 phosphorylation levels largely contribute to BBB impairment. Thus, elevated OSM levels and activation of brain endothelial JAK/STAT3 signaling pathway under pathological conditions should be considered as a possible hallmark for induction and development of BBB impairment.