Review
The pro- and anti-inflammatory properties of the cytokine interleukin-6

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Abstract

Interleukin-6 is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. In classic signaling, interleukin-6 stimulates target cells via a membrane bound interleukin-6 receptor, which upon ligand binding associates with the signaling receptor protein gp130. Gp130 dimerizes, leading to the activation of Janus kinases and subsequent phosphorylation of tyrosine residues within the cytoplasmic portion of gp130. This leads to the engagement of phosphatase Src homology domains containing tyrosin phosphatase-2 (SHP-2) and activation of the ras/raf/Mitogen-activated protein (MAP) kinase (MAPK) pathway. In addition, signal transducer and activator of transcription factors are recruited, which are phosphorylated, and consequently dimerize whereupon they translocate into the nucleus and activate target genes. Interestingly, only few cells express membrane bound interleukin-6 receptor whereas all cells display gp130 on the cell surface. While cells, which only express gp130, are not responsive to interleukin-6 alone, they can respond to a complex of interleukin-6 bound to a naturally occurring soluble form of the interleukin-6 receptor. Therefore, the generation of soluble form of the interleukin-6 receptor dramatically enlarges the spectrum of interleukin-6 target cells. This process has been named trans-signaling. Here, we review the involvement of both signaling modes in the biology of interleukin-6. It turns out that regenerative or anti-inflammatory activities of interleukin-6 are mediated by classic signaling whereas pro-inflammatory responses of interleukin-6 are rather mediated by trans-signaling. This is important since therapeutic blockade of interleukin-6 by the neutralizing anti-interleukin-6 receptor monoclonal antibody tocilizumab has recently been approved for the treatment of inflammatory diseases.

Graphical abstract

Legend:

Cells that express both gp130 and the membrane bound IL-6R are responsive to IL-6 (classic signaling). In contrast, cells that express gp130 but not IL-6R can only be activated by the complex of IL-6 and soluble IL-6R (sIL-6R). Activation of cells by the IL-6/sIL-6R complex is termed trans-signaling. The sIL-6R is generated by proteolytic cleavage of the membrane bound precursor by membrane bound metalloproteases of the ADAM family. The sIL-6R binds IL-6 with comparable affinity as the membrane bound form and mediates gp130 activation in an (1) autocrine or (2) paracrine manner.

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Research Highlights

► The cytokine interleukin-6 (IL-6) has pro- and anti-inflammatory properties. ► Whereas only few cells express the IL-6 receptor and respond to IL-6 (classic signaling), all cells can be stimulated via a soluble IL-6 receptor (trans-signaling) since gp130 is ubiquitously expressed. ► Classic- and trans-signaling can be differentially inhibited. ► Apparently, IL-6 via classic signaling has regenerative and anti-inflammatory functions whereas trans-signaling is pro-inflammatory.

Abbreviations

ADAM
a disintegrin and metalloprotease
AOM
azoxymethane
CBM
cytokine-binding module
DSS
dextran sodium sulfate
Ig
immunoglobulin
IL
interleukin
mAb
monoclonal antibody
mb
membrane bound
R
receptor
STAT
signal transducer and activator of transcription
TNF
tumor necrosis factor
wt
wild type

Keywords

IL-6 trans-signaling
sIL-6R
gp130
sgp130Fc
STAT3 activation
Inflammation associated cancer

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