|PD Dr. Christoph Garbers|
|The major focus of our group is to understand molecular mechanisms which regulate the cell-surface expression of Interleukin (IL-)6 family cytokine receptors, a process that we call cytokine plasticity.|
IL-6 family cytokines are small, glycosylated proteins that can theoretically be secreted by all cells of the human body. They exhibit pro-
as well as anti-inflammatory properties and can act in a systemic or local fashion. IL-6 type cytokines are involved in a variety of physiological
processes, ranging from differentiation and proliferation to apoptosis of their target cells.
Most cytokines bind to their target cells through a unique combination of membrane-bound α- and β-receptors. For instance, IL-11 binds in a first step to the IL-11Rα, and this complex subsequently recruits two gp130 β-receptors, which are the signal-transducing subunits of the IL-11 signaling complex. The Janus kinase (Jak)/Signal Transducer and Activator of Transcription (STAT) pathway is the major intracellular signaling pathway activated, leading to transcription of specific target genes.
In healthy humans, IL-6 family cytokines are only found in very low concentrations or are even completely absent in the serum. However, levels can increase dramatically up to 100,000 fold, especially under inflammatory, pathophysiological conditions. To avoid uncontrolled cytokine signaling, which is itself associated with chronic inflammation, autoimmunity and cancer, cellular expression of cytokine receptors must therefore be tightly controlled and regulated.
|Regulation through limited proteolysis|
Post-translational modifications have a huge impact on protein functions. We are particularly interested in the limited proteolysis (ectodomain shedding)
of membrane-tethered cytokine receptors.
Signaling of IL-6 via the membrane-bound IL-6R is termed classic signaling, whereas signaling via the soluble IL-6R (sIL-6R) has been designated as trans signaling. As the example of the IL-6R illustrates, shedding through the two membrane-bound proteases ADAM10 and ADAM17 results in the generation of a soluble IL-6R (sIL-6R). The sIL-6R binds its ligand IL-6 with similar affinity as the IL-6R on the cell surface, and the IL-6/sIL-6R complex can activate virtually all cells of the human body, since the signal-transducing β-receptor gp130 is ubiquitously expressed. Thus, IL-6R shedding represents a way to generate an agonistic soluble cytokine receptor, which can in complex with its ligand afterwards activate cells that normally are not responsive to IL-6.
Besides this, ectodomain shedding represents a mechanism how cells can down-regulate their cytokine receptor expression, making them unresponsive towards stimulation by the cytokine themselves.
|Transcriptional regulation of cytokine receptor expression|
The cellular expression of cytokine receptors can also be controlled on the transcriptional level. Several stimuli are known that up- or down-regulate mRNA
levels of cytokine receptors like IL-6R and gp130 and thereby influence their expression on the protein level.
It is known for several years that the synthetic glucocorticoid dexamethasone increases IL-6R mRNA and protein levels. We have recently shown that cellular senescence increases IL-6R expression, and that this process was dependent on the activity of mammalian target of rapamycin (mTOR), a serin/threonine kinase that is centrally involved in cell growth, protein synthesis and transcription. Similarly, stimulation of cells with epidermal growth factor (EGF), a known mTOR activator, induced IL-6R mRNA and protein synthesis. Interestingly, dexamethasone induced IL-6R expression independent of mTOR, suggesting a different, yet unknown mechanism.
Soluble gp130 (sgp130) constitutes a natural buffer together with the soluble IL-6R in human blood to prevent uncontrolled actions of IL-6. Several isoforms of sgp130 have been described which originate from differential splicing of the gp130 mRNA. We try to dissect the molecular mechanisms that control sgp130 generation and influence the expression of the different sgp130 isoforms.
|Regulation of intracellular signaling|
After the cytokine has bound to its receptor complex, several intracellular signaling cascades are initiated. In principal, all IL-6 family cytokines activate
the same signaling pathways, namely the Jak/STAT, the MAPK and the PI3K pathway.
Despite these similarities, strength and duration of signaling differ among different cytokines. Our aim is to understand which mechanisms regulate the individual signaling outcome of the single cytokines, and which functional consequences derive from them. Furthermore, we try to identify new kinases, phosphatases and adaptor proteins, which play a role in intracellular signaling induced by IL-6 type cytokines.
|Cytokine receptor plasticity|
Cytokine plasticity can also be found on the level of individual cytokine receptors (see panel A). Gp130 can build homo- and heterodimers and thus serve as
a central signaling module for several different cytokines. IL-6 and IL-11 signal via a gp130 homodimer (plus individual IL-6R/IL-11R). A gp130/LIFR heterodimer
is required for CLC and CNTF (plus CNTFR), whereas CT-1, LIF and OSM do not need any additional receptor for the activation of gp130/LIFR. OSM can furthermore
signal via gp130/OSM. IL-27, which consists of IL-30 and the soluble receptor EBI3, induces the formation of a gp130/WSX-1 heterodimer. Thus, gp130 is able to
bind several different cytokines and receptors via defined contact sites and shows a remarkable plasticity itself.
A second example of plasticity on the level of an individual protein is the IL-6R (see panel B). Besides its main ligand IL-6, CNTF has been shown to bind to the soluble and membrane-bound IL-6R, and that this complex can activate a gp130/LIFR heterodimer. We recently identified a third IL-6R ligand, the IL-27 cytokine subunit IL-30. IL-30 usually heterodimerizes with EBI3 and activates gp130/WSX-1. In complex with either membrane-bound or soluble IL-6R, IL-30 signals via a gp130 homodimer. Thus, the IL-6R acts as a molecular switch to distinguish between gp130/gp130 or gp130/WSX-1 activation in the case of IL-30 signaling.
We are very interested to identify further examples of plasticity and cross-talk between cytokines and cytokine receptors among the IL-6 family of cytokines.
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