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

• Published in: Scientific reports Vol. 9; no. 1; p. 7306
• Main Authors: Flynn, Charlotte M., Garbers, Yvonne, Lokau, Juliane, Wesch, Daniela, Schulte, Dominik M., Laudes, Matthias, Lieb, Wolfgang, Aparicio-Siegmund, Samadhi, Garbers, Christoph
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.05.2019; Nature Publishing Group
• Subjects: 13/21; 13/31; 13/95; 631/250/127/1213; 631/250/516; 631/45/127/1213; 82/1; 96; ADAM10 Protein - metabolism; ADAM17 Protein - metabolism; Alternative splicing; Alternative Splicing - immunology; Amyloid Precursor Protein Secretases - metabolism; Case-Control Studies; Cohort Studies; Cytokines; Extracellular signal-regulated kinase; Flow cytometry; Healthy Volunteers; Humanities and Social Sciences; Humans; Inflammation; Interleukin 6; Interleukin-6 - blood; Interleukin-6 - metabolism; Leukocytes (mononuclear); Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; MAP Kinase Signaling System - immunology; Membrane Proteins - metabolism; Monocytes; Monocytes - immunology; Monocytes - metabolism; mRNA; multidisciplinary; Peripheral blood mononuclear cells; Primary Cell Culture; Proteolysis; Receptors, Interleukin-6 - blood; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - metabolism; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Sepsis - blood; Sepsis - immunology; Signal transduction; THP-1 Cells; TLR2 protein; Toll-Like Receptor 2 - metabolism; Toll-like receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-43617-5

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.