The pro-inflammatory cytokine IL-23 is composed of the IL-12p40 subunit and p19 (1). IL-23 is a key factor for the development of T H 17 cells (2), which control antimicrobial and antifungal responses, but is also critically involved in the pathogenesis of chronic inflammatory disorders (3). The receptor complex is composed of the common IL-12 receptor ␤1 (IL-12 ␤1), 2 shared with IL-12, and the unique IL-23 receptor (4, 5).Single nucleotide polymorphisms within the IL23R gene were associated with various autoimmune diseases and the risk to develop cancer (1). Upon recruitment of the receptors by IL-23, which results in a noncanonical receptor complex formation (6), signaling is initiated by activation of associated Tyk2 (tyrosine kinase 2) and Jak2 (Janus kinase 2), which phosphorylate predominantly STAT3, and to a lesser extent STAT1, STAT4, and STAT5 (5). Recently, a noncanonical tyrosine-independent STAT3 activation site within the IL-23R was identified (7). In addition to STAT proteins PI3K, MAPK and NF-B signaling pathways were activated (7, 28). Ectodomain shedding of membrane-bound proteins leads to receptor protein down-regulation on the cell surface and the generation of soluble protein ectodomains with agonistic or antagonistic properties. Members of the ADAM (A disintegrin and metalloprotease) gene family are major ectodomain shedding proteinases. ADAM17 and its close relative ADAM10 are the major sheddases of this family, (8), with extensive overlap and compensation for several substrates, including EGF receptor ligands, TNF, TNF receptor, and IL-6R (9, 10). Activation of ADAM proteases is achieved by different stimuli including phorbol ester (phorbol-12-myristate-13-acetate (PMA)), ionomycin, ligands of G-protein-coupled receptors, ATP, bacterial toxins, bacterial metalloproteinases, and apoptosis (8). For some ADAM target proteins such as Notch, induction of intracellular signaling by the remaining intracellular domain cleavage product has been described (11). Previously, it was shown that alternative splicing of IL-23R result in a series of truncated soluble .Here, we discovered murine and human IL-23R as novel substrates of ADAM10 and ADAM17, resulting in the release of soluble IL-23R proteins, which retained their ability to bind to IL-23. Distinct areas within the murine and human IL-23R, which are important for ectodomain shedding, were identified in murine and human IL-23R. Immunoprecipitation analysis revealed domains 1 and 3 of IL-23R as critical ADAM17 interaction sites. Thus, we propose that ectodomain shedding is a second mechanism that contributes to the generation of soluble IL-23R variants.

Interleukin 23 (IL-23) regulates the development of TH17 cells, which are important for antimicrobial and antifungal responses and autoimmune and chronic inflammatory diseases. IL-23-induced Jak/STAT signaling is mediated via the heterodimeric IL-23 receptor (IL-23R)-IL-12 receptor ␤1 (IL-12R␤1) complex. The typical signal-transducing receptor of the IL-6/IL-12 family contains three extracellularmembrane-proximal fibronectin type III (FNIII) domains, which are not involved in cytokine binding but are mandatory for signal transduction. In place of FNIII-type domains, IL-23R has a structurally undefined stalk. We hypothesized that the IL-23R stalk acts as a spacer to position the cytokine binding domains at a defined distance from the plasma membrane to enable signal transduction. Minor deletions of the murine, but not of the human, IL-23R stalk resulted in unresponsiveness to IL-23. Complete deletion of the human IL-23R stalk and the extended murine IL-23R stalk, including a 20-amino-acid-long duplication of domain 3, however, induced ligandindependent, autonomous receptor activation, as determined by STAT3 phosphorylation and cell proliferation. Ligand-independent, autonomous activity was caused by IL-23R homodimers and was independent of IL-12R␤1. Our data show that deletion of the stalk results in biologically active IL-23R homodimers, thereby creating an asyet-undescribed receptor complex of the IL-6/IL-12 cytokine family.KEYWORDS IL-23 receptor, IL-23 signaling T he proinflammatory cytokine interleukin 23 (IL-23) is a member of the IL-6/IL-12 family (1). IL-23 regulates the development of TH17 cells, which are important mediators of antimicrobial and antifungal responses. Furthermore, they are involved in the pathogenesis of autoimmune and chronic inflammatory diseases (2). IL-23 binding initiates the heterodimerization of the ␤ receptor chains IL-23 receptor (IL-23R) and IL-12R␤1. Subsequently, receptor-associated tyrosine kinase 2 (Tyk2) and Janus kinase 2 (Jak2) activate independent signaling pathways, including the Jak/STAT, the mitogenactivated protein kinase (MAPK)/Erk, and the phosphatidylinositol 3-kinase (PI3K)/Akt pathways. IL-23 predominantly activates STAT3 and to a lesser extent STAT1, STAT4, and STAT5 (3, 4).IL-12R␤1 was considered a ligand binding receptor (5). However, it was demonstrated that IL-12R␤1 is important for kinase binding and activation. Moreover, association of Jak2 with IL-23R is mandatory for IL-23 signaling, whereas Tyk2 seems to be dispensable (6).IL-23R is composed of an N-terminal immunoglobulin-like domain 1 (D1) and a cytokine binding module (CBM) formed by domains 2 and 3 (D2 and D3), which carry