ID: 94: Shedding of the IL-23 receptor by metalloproteases
The heterodimeric cytokine Interleukin 23 (IL-23), which consists of the unique subunit p19 and the shared subunit p40, is important for the differentiation and maintenance of TH17 cells. TH17 cells produce the pro-inflammatory cytokine IL-17 and mediate the clearance of pathogens during infections. IL-23 plays a crucial role in autoimmune diseases and tumor development. IL-23 signalling occurs via the unique IL-23R and the IL-12R β 1, which is shared with IL-12. Differential splicing generates antagonistic soluble IL-23R variants. However, protein ectodomain shedding of IL-23 has not been described so far. We initiated analyses to investigate the shedding of this receptor. Here, we found that both human and murine IL-23R are targets of ectodomain shedding, resulting in the generation of soluble IL-23R. Shed soluble IL-23R can form complexes with IL-23. IL-23R is shed after stimulation by the phorbol ester PMA, but not by Ionomycin. Furthermore shedding can be reduced by GW280264X, which is an inhibitor of ADAM10 and ADAM17 but not by the ADAM10 specific inhibitor GI254023X. Our data indicates that ADAM17 is the main sheddase of the IL-23R. Furthermore IL-23R is shed constitutively. Constitutive shedding was inhibited by GI254023X and GW280264X, suggesting that ADAM10 mediates constitutive shedding of the IL-23R. Finally, using stalk-deletion-variants, we identified the regions within the murine and human IL-23R, which are important for ectodomain shedding.