Journal
CELL COMMUNICATION AND SIGNALING
Volume 16, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12964-018-0268-4
Keywords
Interleukin-6 signaling; Monocyte chemoattractant Protein-1; Pro-inflammatory cytokines; Endothelium; HUVECs
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Funding
- Knowledge Foundation
- Langmanska Foundation
- Foundation for Old Servants (Stiftelsen Gamla Tjanarinnor)
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Background: IL-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. Methods: In 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). Results: We 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. Conclusions: Collectively, 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.
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