The cytokine interleukin-6 (IL-6) is involved in health and disease (Figure 1). In many diseases, IL‑6 is overproduced and needs to be controlled either by inhibition of its unbalanced production or by blocking its action on the surface receptors of target cells. Therefore, it is important to understand the molecular mechanism underlying interleukin-6 signal transduction in detail. Also, the successful design of IL-6 antagonists is of great interest.
IL-6 is a cytokine with many biological activities (Figure 2).
IL-6 forms a hexameric signalling receptor complex composed of two alpha-receptors (IL‑6R), two gp130 signal transducers and two IL-6 ligands (Figure 3).
The IL-6 signal transduction occurs via the JAK/ STAT pathway, i.e. tyrosine kinases of the Janus family activate signal transducers and activators of transcription. In the case of IL-6 signalling, STAT3 is the transcription factor of prime importance (Figure 4).
In order not to overstimulate a target cell, cytokine initiated signalling needs to be turned off. In the case of IL-6, this is achieved by many mechanisms as shown in figure 5. The most important negative regulatory mechanisms are exerted by the tyrosine phosphatase SHP2 and by the induction – via the JAK/ STAT pathway – of feedback inhibitors, the so called suppressors of cytokine signalling (SOCS), in the case of IL-6 mainly by SOCS3.
Figure 6 summarizes schematically various projects of the group leaders (I. Behrmann, S. Haan, H.M. Hermanns, G. Müller-Newen, F. Schaper) of the Heinrich group at the Institute of Biochemistry in Aachen during the last six years’ period from 2002 until 2007.