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

被引:47
作者
Flynn, Charlotte M. [1 ]
Garbers, Yvonne [2 ]
Lokau, Juliane [1 ,6 ]
Wesch, Daniela [3 ]
Schulte, Dominik M. [4 ]
Laudes, Matthias [4 ]
Lieb, Wolfgang [5 ]
Aparicio-Siegmund, Samadhi [1 ]
Garbers, Christoph [1 ,6 ]
机构
[1] Univ Kiel, Inst Biochem, Kiel, Germany
[2] Univ Kiel, Inst Psychol, Kiel, Germany
[3] Univ Hosp Schleswig Holstein, Inst Immunol, Campus Kiel, Kiel, Germany
[4] Univ Kiel, Dept Internal Med 1, Kiel, Germany
[5] Univ Kiel, Inst Epidemiol, Kiel, Germany
[6] Otto von Guericke Univ, Med Fac, Dept Pathol, Magdeburg, Germany
关键词
NF-KAPPA-B; SOLUBLE IL-6R; CUTTING EDGE; BLOCKADE; BIOLOGY; GENE; EXPRESSION; CYTOKINE; ADAM10; SERUM;
D O I
10.1038/s41598-019-43617-5
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:11
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