Activation of Toll-like Receptor 2 (TLR2) induces Interleukin-6 trans-signaling.

TitelActivation of Toll-like Receptor 2 (TLR2) induces Interleukin-6 trans-signaling.
MedientypJournal Article
Jahr der Veröffentlichung2019
AutorenFlynn CM, Garbers Y, Lokau J, Wesch D, Schulte DM, Laudes M, Lieb W, Aparicio-Siegmund S, Garbers C
JournalSci Rep
Volume9
Ausgabe1
Pagination7306
Datum der Veröffentlichung2019 May 13
ISSN2045-2322
Zusammenfassung

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.

DOI10.1038/s41598-019-43617-5
Alternate JournalSci Rep
PubMed ID31086276
PubMed Central IDPMC6513869
Grant ListEXC306/2 / / Deutsche Forschungsgemeinschaft (German Research Foundation) /
“InTraSig”, project B / / Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research) /