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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
Örebro University, School of Medical Sciences. (Cardiovascular Research Center)ORCID iD: 0000-0001-6952-8952
Örebro University, School of Medical Sciences. (Cardiovascular Research Center)
Örebro University, School of Medical Sciences. (Cardiovascular Research Center)ORCID iD: 0000-0003-2519-203X
Örebro University, School of Medical Sciences. (Cardiovascular Research Center)ORCID iD: 0000-0002-2244-9816
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2018 (English)In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 16, no 1, article id 55Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central, 2018. Vol. 16, no 1, article id 55
Keywords [en]
Endothelium, HUVECs, Interleukin-6 signaling, Monocyte chemoattractant Protein-1, Pro-inflammatory cytokines
National Category
Cell and Molecular Biology
Research subject
Physical Education and Sport Pedagogy; Physical Education and Sport Pedagogy
Identifiers
URN: urn:nbn:se:oru:diva-68803DOI: 10.1186/s12964-018-0268-4ISI: 000443839900001PubMedID: 30185178Scopus ID: 2-s2.0-85053157310OAI: oai:DiVA.org:oru-68803DiVA, id: diva2:1246699
Funder
Knowledge Foundation
Note

Funding Agencies:

Längmanska Foundation  

Foundation for Old Servants (Stiftelsen Gamla Tjänarinnor)  

Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2019-03-26Bibliographically approved

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Zegeye, Mulugeta M.Lindkvist, MadeleneFälker, KnutKumawat, Ashok K.Paramel Varghese, GeenaGrenegård, MagnusSirsjö, AllanLjungberg, Liza U.

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Zegeye, Mulugeta M.Lindkvist, MadeleneFälker, KnutKumawat, Ashok K.Paramel Varghese, GeenaGrenegård, MagnusSirsjö, AllanLjungberg, Liza U.
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Cell Communication and Signaling
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