Hitting a complex target:  an update on interleukin-6  trans-signalling.
BACKGROUND
Interleukin-6 (IL-6) is a key target in inflammation and cancer. Selective inhibition of IL-6 trans-signalling could provide the same or even higher therapeutic efficacy with a better side effect profile than complete IL-6 inhibition. Animal studies with IL-6 inhibitors show that the classic IL-6 signalling pathway via the membrane-bound IL-6 receptor (IL-6R) has important physiological functions, whereas blocking the trans-signalling pathway via the soluble IL-6R (sIL-6R) is sufficient to prevent or treat IL-6-driven diseases. Due to the success of the anti-IL-6R antibody tocilizumab and difficulties of constructing selective trans-signalling inhibitors, most drug candidates in clinical development target IL-6 or IL-6R and, thus, both IL-6 pathways. By contrast, the fusion protein sgp130Fc selectively targets IL-6/sIL-6R trans-signalling by utilising the soluble gp130 receptor as the natural inhibitor of trans-signalling.


METHODS
The authors summarise recent developments in the field with a focus on animal studies highlighting the mechanistic differences between classic and trans-signalling and their therapeutic implications.


CONCLUSIONS
Characterising disease mechanisms in terms of the employed IL-6 pathways will help to select the right therapeutic IL-6 inhibitor in the future. The trans-signalling inhibitor sgp130Fc is about to enter the clinic and holds promise for a clinically different profile in comparison with complete IL-6 inhibitors.
Christian-Albrechts-University Kiel, Institute of Biochemistry, Kiel, Germany.
Georg H
GH
Waetzig
Stefan
S
Rose-John
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D019947:Receptors, Interleukin-6 / Q000276:immunology; D015398:Signal Transduction; D000093242:Interleukin-6 Inhibitors
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors