Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells

Abstract

BackgroundIL-6 classic signaling is linked to anti-inflammatory functions while the trans-signaling is associated with pro-inflammatory responses. Classic signaling is induced via membrane-bound IL-6 receptor (IL-6R) whereas trans-signaling requires prior binding of IL-6 to the soluble IL-6R. In both cases, association with the signal transducing gp130 receptor is compulsory. However, differences in the downstream signaling mechanisms of IL-6 classic- versus trans-signaling remains largely elusive.MethodsIn this study, we used flow cytometry, quantitative PCR, ELISA and immuno-blotting techniques to investigate IL-6 classic and trans-signaling mechanisms in Human Umbilical Vein Endothelial Cells (HUVECs).ResultsWe show that both IL-6R and gp130 are expressed on the surface of human vascular endothelial cells, and that the expression is affected by pro-inflammatory stimuli. In contrast to IL-6 classic signaling, IL-6 trans-signaling induces the release of the pro-inflammatory chemokine Monocyte Chemoattractant Protein-1 (MCP-1) from human vascular endothelial cells. In addition, we reveal that the classic signaling induces activation of the JAK/STAT3 pathway while trans-signaling also activates the PI3K/AKT and the MEK/ERK pathways. Furthermore, we demonstrate that MCP-1 induction by IL-6 trans-signaling requires simultaneous activation of the JAK/STAT3 and PI3K/AKT pathways.ConclusionsCollectively, our study reports molecular differences in IL-6 classic- and trans-signaling in human vascular endothelial cells; and elucidates the pathways which mediate MCP-1 induction by IL-6 trans-signaling.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0268-4) contains supplementary material, which is available to authorized users.

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“…IL‐6 trans‐signalling can lead to JAK/STAT and ERK1/2 phosphorylation . To investigate whether LMT‐28 inhibited the IL‐6/sIL‐6R signalling pathway, we tested whether Hyper‐IL‐6, an IL‐6/sIL‐6R fusion protein, could induce phosphorylation of STAT3 and ERK in condition with/without LMT‐28 in RA‐FLS.…”

“…IL-6 trans-signalling can lead to JAK/STAT and ERK1/2 phosphorylation. [21][22][23][24] To investigate whether LMT-28 inhibited the IL-6/sIL-6R signalling pathway, we tested whether Hyper-IL-6, an IL-6/sIL-6R fusion protein (provided by Dr. Stefan Rose-John (University of Kiel, Germany)), could induce phosphorylation of STAT3 and ERK in condition with/without LMT-28 in RA-FLS. LMT-28 dose-dependently inhibited phosphorylation of STAT3 and ERK in RA-FLS ( Figure 5B).…”

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“…The trans presentation signal is suppressed by extracellular sgp130, and sgp130 can form a complex with sIL-6R to prevent sIL-6R from binding to membrane-bound gp130 [16]. The next step is to activate the JAK-STATA (STAT1, STAT3 and, to a lesser extent, STAT5) pathway [22][23][24][25], in addition, RAS-RAF pathway [23,26], SRC-YAP-NOTCH pathway [27], and AKT-PI3K pathway [28,29] also being activated(Figure3D). So as to promote complex biological functions such as proliferation, differentiation, oxidative stress, immune regulation and so on [16].…”

Rational Use of Tocilizumab in the Treatment of Novel Coronavirus Pneumonia

“…One IL-6 signaling pathway is mediated by the JAK/STAT tyrosine kinase system, while the other is mediated by the Ras/mitogenactivated protein kinase (MAPK)/NF-κB-IL-6 pathway. The former is a major pathway [25,26].…”