PMID- 30185178
OWN - NLM
STAT- MEDLINE
DCOM- 20190510
LR  - 20190510
IS  - 1478-811X (Electronic)
IS  - 1478-811X (Linking)
VI  - 16
IP  - 1
DP  - 2018 Sep 5
TI  - 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.
PG  - 55
LID - 10.1186/s12964-018-0268-4 [doi]
LID - 55
AB  - 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.
FAU - Zegeye, Mulugeta M
AU  - Zegeye MM
AUID- ORCID: 0000-0001-6952-8952
AD  - Cardiovascular Research Center, School of Medical Sciences, Orebro University 
      Sodra Grev Rosengatan 32, 703 62, Orebro, Sweden. mulugeta.m.zegeye@oru.se.
FAU - Lindkvist, Madelene
AU  - Lindkvist M
AD  - Cardiovascular Research Center, School of Medical Sciences, Orebro University 
      Sodra Grev Rosengatan 32, 703 62, Orebro, Sweden.
FAU - Falker, Knut
AU  - Falker K
AD  - Cardiovascular Research Center, School of Medical Sciences, Orebro University 
      Sodra Grev Rosengatan 32, 703 62, Orebro, Sweden.
FAU - Kumawat, Ashok K
AU  - Kumawat AK
AD  - Cardiovascular Research Center, School of Medical Sciences, Orebro University 
      Sodra Grev Rosengatan 32, 703 62, Orebro, Sweden.
FAU - Paramel, Geena
AU  - Paramel G
AD  - Cardiovascular Research Center, School of Medical Sciences, Orebro University 
      Sodra Grev Rosengatan 32, 703 62, Orebro, Sweden.
AD  - Present address: Department of Biochemistry and Molecular Biology, Faculty of 
      Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, 
      E2L 4L5, Canada.
FAU - Grenegard, Magnus
AU  - Grenegard M
AD  - Cardiovascular Research Center, School of Medical Sciences, Orebro University 
      Sodra Grev Rosengatan 32, 703 62, Orebro, Sweden.
FAU - Sirsjo, Allan
AU  - Sirsjo A
AD  - Cardiovascular Research Center, School of Medical Sciences, Orebro University 
      Sodra Grev Rosengatan 32, 703 62, Orebro, Sweden.
FAU - Ljungberg, Liza U
AU  - Ljungberg LU
AD  - Cardiovascular Research Center, School of Medical Sciences, Orebro University 
      Sodra Grev Rosengatan 32, 703 62, Orebro, Sweden.
LA  - eng
GR  - 20150245 and 20120213/Knowledge Foundation/International
GR  - K-70 31/15/Langmanska Foundation/International
GR  - 2014-00147 and 2015-00248/Stiftelsen for Gamla Tjanarinnor/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180905
PL  - England
TA  - Cell Commun Signal
JT  - Cell communication and signaling : CCS
JID - 101170464
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-6)
RN  - 0 (STAT3 Transcription Factor)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.2 (Janus Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Chemokine CCL2/metabolism
MH  - Endothelial Cells/metabolism/*pathology
MH  - Gene Expression Regulation
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Inflammation/metabolism/pathology
MH  - Interleukin-6/*metabolism
MH  - Janus Kinases/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - STAT3 Transcription Factor/*metabolism
MH  - *Signal Transduction
PMC - PMC6125866
OTO - NOTNLM
OT  - Endothelium
OT  - HUVECs
OT  - Interleukin-6 signaling
OT  - Monocyte chemoattractant Protein-1
OT  - Pro-inflammatory cytokines
COIS- CONSENT FOR PUBLICATION: Not applicable COMPETING INTERESTS: The authors declare 
      that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains 
      neutral with regard to jurisdictional claims in published maps and institutional 
      affiliations.
EDAT- 2018/09/07 06:00
MHDA- 2019/05/11 06:00
PMCR- 2018/09/05
CRDT- 2018/09/07 06:00
PHST- 2018/06/04 00:00 [received]
PHST- 2018/08/27 00:00 [accepted]
PHST- 2018/09/07 06:00 [entrez]
PHST- 2018/09/07 06:00 [pubmed]
PHST- 2019/05/11 06:00 [medline]
PHST- 2018/09/05 00:00 [pmc-release]
AID - 10.1186/s12964-018-0268-4 [pii]
AID - 268 [pii]
AID - 10.1186/s12964-018-0268-4 [doi]
PST - epublish
SO  - Cell Commun Signal. 2018 Sep 5;16(1):55. doi: 10.1186/s12964-018-0268-4.