Activation of Toll-like Receptor 2 (TLR2) induces Interleukin-6 trans-signaling.
ADAM10 Protein
/ metabolism
ADAM17 Protein
/ metabolism
Alternative Splicing
/ immunology
Amyloid Precursor Protein Secretases
/ metabolism
Case-Control Studies
Cohort Studies
Healthy Volunteers
Humans
Interleukin-6
/ blood
Leukocytes, Mononuclear
/ immunology
MAP Kinase Signaling System
/ immunology
Membrane Proteins
/ metabolism
Monocytes
/ immunology
Primary Cell Culture
RNA, Messenger
/ metabolism
Receptors, Interleukin-6
/ blood
Sepsis
/ blood
THP-1 Cells
Toll-Like Receptor 2
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
13 05 2019
13 05 2019
Historique:
received:
15
10
2018
accepted:
27
04
2019
entrez:
16
5
2019
pubmed:
16
5
2019
medline:
30
10
2020
Statut:
epublish
Résumé
Signaling of the pleiotropic cytokine Interleukin-6 (IL-6) via its soluble IL-6R (sIL-6R) has been termed trans-signaling and is thought to be responsible for the pro-inflammatory properties of IL-6. The sIL-6R can be generated by alternative mRNA splicing or proteolytic cleavage of the membrane-bound IL-6R. However, which stimuli induce sIL-6R release and which endogenous signaling pathways are required for this process is poorly understood. Here, we show that activation of Toll-like receptor 2 (TLR2) on primary human peripheral blood mononuclear cells (PBMCs) and on the monocytic cell line THP-1 induces expression and secretion of IL-6 and the generation of sIL-6R. We show by flow cytometry that monocytes are a PBMC subset that expresses TLR2 in conjunction with the IL-6R and are the major cellular source for both IL-6 and sIL-6R. Mechanistically, we find that the metalloproteases ADAM10 and ADAM17 are responsible for cleavage of the IL-6R and therefore sIL-6R generation. Finally, we identify the Extracellular-signal Regulated Kinase (ERK) cascade as a critical pathway that differentially regulates both IL-6 and sIL-6R generation in monocytes.
Identifiants
pubmed: 31086276
doi: 10.1038/s41598-019-43617-5
pii: 10.1038/s41598-019-43617-5
pmc: PMC6513869
doi:
Substances chimiques
IL6 protein, human
0
IL6R protein, human
0
Interleukin-6
0
Membrane Proteins
0
RNA, Messenger
0
Receptors, Interleukin-6
0
TLR2 protein, human
0
Toll-Like Receptor 2
0
Amyloid Precursor Protein Secretases
EC 3.4.-
ADAM10 Protein
EC 3.4.24.81
ADAM10 protein, human
EC 3.4.24.81
ADAM17 Protein
EC 3.4.24.86
ADAM17 protein, human
EC 3.4.24.86
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7306Références
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