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

  • Cell Commun Signal. 2018 Sep 5;16(1):55. doi: 10.1186/s12964-018-0268-4.
Mulugeta M Zegeye  1 ,  Madelene Lindkvist  2 ,  Knut Fälker  2 ,  Ashok K Kumawat  2 ,  Geena Paramel  2  3 ,  Magnus Grenegård  2 ,  Allan Sirsjö  2 ,  Liza U Ljungberg  2
Affiliations
  • 1. Cardiovascular Research Center, School of Medical Sciences, Örebro University Södra Grev Rosengatan 32, 703 62, Örebro, Sweden. [email protected].
  • 2. Cardiovascular Research Center, School of Medical Sciences, Örebro University Södra Grev Rosengatan 32, 703 62, Örebro, Sweden.
  • 3. Present address: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, E2L 4L5, Canada.
PMID: 30185178 DOI: 10.1186/s12964-018-0268-4
Abstract

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.

Keywords
Endothelium; HUVECs; Interleukin-6 signaling; Monocyte chemoattractant Protein-1; Pro-inflammatory cytokines.