Oncostatin M–induced blood‐brain barrier impairment is due to prolonged activation of STAT3 signaling in vitro

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. Our findings suggest that OSM is the most potent molecule for impairing BBB integrity among IL‐6 family cytokines including IL‐6 and LIF. OSM induces BBB impairment through persistently high activation of the JAK/STAT3 signaling pathway. IL‐6 and LIF show transient low STAT3 activation compared with OSM, resulting in less or no activity against BBB function. Duration and levels of STAT3 activation may be a determinant factor for OSM‐induced BBB impairment.