Human and Murine Interleukin 23 Receptors Are Novel Substrates for A Disintegrin and Metalloproteases ADAM10 and ADAM17

Franke, Manuel; Schröder, Jutta; Monhasery, Niloufar; Ackfeld, Theresa; Hummel, Thorben M.; Rabe, Björn; Garbers, Christoph; Becker‐Pauly, Christoph; Floß, Doreen M.; Scheller, Jürgen

doi:10.1074/jbc.m115.710541

Cited by 21 publications

(28 citation statements)

References 28 publications

(43 reference statements)

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“…p40 also binds to p28 to form p28/p40, tentatively called IL-Y, but this complex was demonstrated to be an antagonist to the signaling by IL-12 and IL-27 (15, 16). In addition, biological activities of monomeric forms of p28 (17), EBI3 (18), and p19 (19) and generation of soluble receptors of WSX-1 (20) and IL-23R (21) as antagonists to IL-27 and IL-23, respectively, were reported as well.…”

Section: Introductionmentioning

confidence: 99%

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

et al. 2016

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The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they comprise two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than six cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein–Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses, such as helper T (Th)1, Th2, and Th17, to anti-inflammatory responses, such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells, such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus, promiscuity within the IL-6/IL-12 family cytokines complicates structural and functional clarification and assignment of individual cytokines. A better understanding of the recent advances and expanding diversity in molecular structures and functions of the IL-6/IL-12 family cytokines could allow the creation of novel therapeutic strategies by using them as tools and targeted molecules.

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Section: Introductionmentioning

confidence: 99%

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

et al. 2016

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“…Ba/F3 cells were grown in 0.2% conditioned medium of WEHI-3B cells (DSMZ ACC-26). Generation of Ba/F3-gp130 cell lines with murine and human IL-12R␤1 and IL-23R was described previously (3,8). Ba/F3-gp130 cells were maintained in the presence of HIL-6, a fusion protein of IL-6 and the soluble IL-6R, which mimics IL-6 trans signaling (16).…”

Section: Methodsmentioning

confidence: 99%

“…Generation of the eukaryotic expression vector p409 (46) and the retroviral plasmids pMOWS-puro and pMOWS-hygro (20) containing the cDNA encoding murine or human receptors was described previously (3). Corresponding expression vectors for the IL-23R stalk deletion variants were cloned according a method described previously (8). N-terminally FLAG-tagged receptors and C-terminally myc-tagged IL-23R lacking the extracellular domain were generated by splicing with overlap extension PCR (SOE-PCR).…”

Section: Methodsmentioning

confidence: 99%

“…The IL-23R stalk region is unique among the signal-transducing receptors of the IL-6/IL-12-type family and contains critical determinants of ectodomain shedding mediated by ADAM10 and ADAM17. Recently, we demonstrated, using stalk deletion variants, that the ADAM17 cleavage site is located in the area of amino acid residues 333 to 342 of murine IL-23R and in the area of amino acid residues 323 to 333 of human IL-23R (hIL-23R) (8). Only the nonsignaling IL-6R contains a comparably long stalk region, which is also a target for ADAM proteases (9).…”

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Synthetic Deletion of the Interleukin 23 Receptor (IL-23R) Stalk Region Led to Autonomous IL-23R Homodimerization and Activation

Hummel

Ackfeld

Schönberg

et al. 2017

Molecular and Cellular Biology

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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

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“…IL-23 22. Por otra parte, se sabe que el IL-23R murino y humano son sustratos de ADAM10 y ADAM17, dando como resultado la liberación del IL-23R solubles que tiene la capacidad de unirse a la IL-23 24. …”

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Relación de la periodontitis y artritis reumatoide a través del eje IL-23/IL-17A

Rodríguez-Montaño¹,

Aguilar-Carrillo²,

Bernard-Medina³

et al. 2019

Revista Mexicana De Periodontología

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Revisión bibliogRáfica RESUMEN La artritis reumatoide (AR) y la periodontitis (P) son enfermedades inflamatorias crónicas. De manera reciente, se ha descrito que 90% de los pacientes con AR presentan P. Ambas patologías se caracterizan por la destrucción de la articulación y el hueso alveolar, respectivamente. Se sabe que 1% de la población mundial presenta artilugios y en México es el 1.6%. Sobre la periodontitis, su prevalencia es de 15 a 20% de la población mundial y en México es de 60%. La etiología de ambas enfermedades es similar, ya que son multifactoriales y comparten varios factores de riesgo que pueden desencadenarlas, como lo son factores genéticos, biológicos o ambientales, dentro de los cuales uno de los que mantiene más cercana la relación de estas enfermedades es el factor biológico, donde una disbiosis a nivel bucal o intestinal puede comenzar con inflamación local y a su vez sistemática. Las citocinas proinflamatorias IL-23 e IL-17 y sus receptores juegan un papel muy importante en la inmunopatología de estas enfermedades. IL-23 activa y expande los clones Th17 a través de IL-23R y promueve la producción de IL-17 y RANKL; sin embargo, la IL-23R soluble puede bloquear el receptor de IL-23 al inhibir su señalización. IL-17 a través de IL-17RA puede activar fibroblastos y macrófagos que expresan RANKL que activa los precursores de osteoclastos e inicia la erosión ósea en las articulaciones y el hueso alveolar. Al igual que el receptor soluble de IL-23R, el ser soluble de IL-17RA puede bloquear a IL-17A e inhibir su señalización.

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Human and Murine Interleukin 23 Receptors Are Novel Substrates for A Disintegrin and Metalloproteases ADAM10 and ADAM17

Cited by 21 publications

References 28 publications

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

Synthetic Deletion of the Interleukin 23 Receptor (IL-23R) Stalk Region Led to Autonomous IL-23R Homodimerization and Activation

Relación de la periodontitis y artritis reumatoide a través del eje IL-23/IL-17A

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