Dokument: Funktionelle Charakterisierung der site II Interaktion zwischen IL-12/IL-23p40 und IL-12Rb1
| Titel: | Funktionelle Charakterisierung der site II Interaktion zwischen IL-12/IL-23p40 und IL-12Rb1 | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=69043 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250320-080516-6 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Georgy, Jacqueline [Autor] | |||||||
| Dateien: |
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| Beitragende: | PD Dr. Floß, Doreen M. [Gutachter] Dr. Scheu, Stefanie [Gutachter] Prof. Dr. rer. nat. Zielonka, Stefan [Gutachter] | |||||||
| Stichwörter: | IL-12, IL-23, IL-12Rb1, IL-23R, IL-12Rb2, STAT, ERK, Siganltransduktion, Protein-Protein-Interaktion, site I-II-III Paradigma | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Interleukin (IL)-12 und IL-23 sind proinflammatorische Zytokine der IL-12 Familie und sind strukturell ähnlich aufgebaut. Allerdings haben sie unterschiedliche Funktionen im Immunsystem. Währenddessen IL-12 an der Differenzierung von TH1-Zellen und an der Abwehr von Tumorzellen beteiligt ist, spielt IL-23 bei der Regulierung der TH17-Antwort und bei der Pathogenese verschiedener Autoimmunkrankheiten eine entscheidende Rolle.
IL-12 (p35/p40) und IL-23 (p19/p40) bestehen beide aus der gemeinsamen β-Untereinheit p40 und einer zytokinspezifischen α-Untereinheit, p35 oder p19. Die Signaltransduktion erfolgt über den gemeinsamen IL-12 Rezeptor β1 (IL-12Rβ1) und den zytokinspezifischen IL-12 Rezeptor β2 (IL-12Rβ2) oder IL-23 Rezeptor (IL-23R). Die Signaltransduktion von IL-12 und IL-23 führt u.a. zur Aktivierung des JAK-STAT-Weges und MAPK-Weges. In Abwesenheit von der α-Untereinheit kann p40 Homodimere bilden, die p80 genannt werden. Der Aufbau des IL-12 und IL-23 Zytokinrezeptorkomplex folgt dem site I-II-III Paradigma mit einer nicht-kanonischen site II. Im IL-23 Zytokinrezeptorkomplex bindet p19 über site I an p40. Die Interaktion von p19 mit dem IL-23R erfolgt über site III. An site II ist p19 nicht beteiligt. Stattdessen interagiert p40 mit IL-12Rβ1. Für site I und site III konnten bereits kritische Aminosäuren identifiziert werden. Des Weiteren konnten durch Mutation einzelner kritischer Aminosäuren von site I und site III inaktive IL-12 und IL-23 Varianten generiert werden. Es konnten bereits kritische Aminosäuren in p40 für die site II Interaktion identifiziert werden: H216, K217, K219, W37 und F82. Um eine inaktive IL-23 Variante zu generieren, wurde zunächst die N-terminale Domäne von Hyper-IL-23, einem Fusionsprotein aus p19 und p40, näher analysiert. Nach der Stimulation von Ba/F3-gp130-mIL-12Rβ1-mIL-23R-Zellen mit konditionierten Zellkulturüberständen der p40-Deletionsvariante ΔM23-P39 im HIL-23 Fusionsprotein zeigte sich keine Proliferation der Zellen und keine Aktivierung der intrazellulären Signalwege. Des Weiteren kann ΔM23-P39 im HIL-23 Fusionsprotein nicht den IL-12Rβ1 binden. Daher sollten durch Generierung verschiedener Mutationen die N-terminalen Aminosäuren von p40 analysiert werden. Durch Punktmutation von Tryptophan 37 zu Lysin (W37K) in p40 konnte die Proliferation von Ba/F3-gp130-mIL-12Rβ1-mIL-23R-Zellen und die Aktivierung der intrazellulären Signalwege signifikant reduziert werden. Auch konnte p40 W37K nicht an IL-12Rβ1 binden. Durch Kombination der Punktmutationen W37K in p40 mit den benachbarten Aminosäuren D36K und T38K in p40 von HIL-23 und HIL-12 wurden inaktive IL-23 und IL-12 Varianten generiert, die weder die zelluläre Proliferation noch die Aktivierung von intrazellulären Signalwegen induzieren konnten. Auch wurde keine Interaktion mit dem IL-12Rβ1 nachgewiesen. P40 Homodimere, p80, binden mit hoher Affinität an IL-12Rβ1, allerdings konnte bisher keine funktionelle Aktivität des IL-12Rβ1 Homodimer gezeigt werden. P80 kann unter bestimmten Bedingungen die Signaltransduktion von IL-12 und IL-23 inhibieren. Nach Einbringung der Mutationen D36K/W37K/T38K in p80 zeigte sich keine Inhibition der Signaltransduktion von IL-12 und IL-23. Zusammenfassend wurde W37 in p40 als kritische Aminosäure der site II zwischen p40 und dem IL-12Rβ1 bestätigt und die Mutationen p40 D36K/W37K/T38K führte in IL-12, IL-23 und p80 zu einer inaktiven Variante. Genaue Kenntnisse über den Aufbau des IL-12 und IL-23 Zytokinrezeptorkomplexes und für die Interaktion wichtige Aminosäuren können neue Ansatzpunkte in der Therapie von Krebs und Autoimmunkrankheiten darstellen.IL-12 and IL-23 are proinflammatory cytokines and members of the IL-12 family. They have a similar structure but different functions in the immune system. IL-12 is involved in the differentiation of TH1-cells and in defense of tumor cells. IL-23 is important for TH17-cell differentiation and plays an important role in the pathogenesis of autoimmune diseases. IL-12 (p35/p40) and IL-23 (p19/p40) consist of the common β-subunit p40 and the specific α- subunit p35 or p19. IL-12 and IL-23 signal via the common IL-12 receptor β1 (IL-12Rβ1) and the specific IL-12 receptor β2 (IL-12Rβ2) or IL-23 receptor (IL-23R). For example, they activate the JAK-STAT pathway and the MAPK pathway. In absence of p19 and p35, p40 can form homodimers, which are called p80. Structure of IL-12 and IL-23 cytokine receptor complex follows the site I-II-III paradigm with a non-canonical site II interaction. In the IL-23 cytokine receptor complex p19 binds to p40 via site I and p19 binds to IL-23R via site III. The α-subunit p19 is not part of site II interaction. Instead, p40 binds to IL-12Rβ1 via site II. Critical amino acids have been identified for site I and III interaction. Point mutations of critical site I and site III amino acids led to inactive IL-12 and IL-23 variants. In p40 critical amino acids for site II interaction have been identified: H216, K217, K219, W37 and F82. To generate an inactive site II variant, the N-terminal region of Hyper IL-23, a fusion protein combining p40 and p19, has been analysed. Ba/F3-gp130-mIL-12Rβ1-mIL-23R cells did not proliferate and intracellular pathways were not activated after stimulation with p40 deletion variant ΔM23-P39 in fusion protein HIL-23. In co-immunoprecipitation studies ΔM23-P39 in HIL-23 does not interact with IL-12Rβ1. Hence, amino acids of the N-terminal domain in p40 should be analysed through generation of point mutants in p40. Proliferation of Ba/F3-gp130-mIL-12Rβ1-mIL-23R cells and activation of signaling pathway was significantly reduced after stimulation with cell culture supernatant of W37 mutated p40. In co-immunoprecipitation studies HIL-23 W37 does not interact with IL-12Rβ1. Combination of W37K in p40 with point mutations of surrounding amino acids D36K and T38K in p40 leds to an inactive IL-12 and IL-23 variant, which could not induce proliferation and activation of signaling pathways and does not interact with IL-12Rβ1. P40 homodimers, p80, bind with high affinity to IL-12Rβ1. In functional analysis, IL-12Rβ1 homodimers are not biologically active. Under specific conditions p80 inhibits signal transduction of IL-12 and IL-23. p80 D36K/W37K/T38K could not inhibit signal transduction of IL-12 and IL-23. Summarizing, p40W37 was confirmed as a critical amino acid for site II interaction with IL-12Rβ1. Interestingly, HIL-23 D36K/W37K/T38K, HIL-12 D36K/W37K/T38K and p80 D36K/W37K/T38K were identified as inactive IL-23, IL-12 and p80 variants. Precise knowledge of the structure of IL-23 and IL-12 cytokine receptor complex is important to develop therapeutic strategies against autoimmune diseases and cancer. | |||||||
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| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 20.03.2025 | |||||||
| Dateien geändert am: | 20.03.2025 | |||||||
| Promotionsantrag am: | 23.08.2024 | |||||||
| Datum der Promotion: | 11.03.2025 |
