Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10
| Autor: | Leon Su, Robert A. Saxton, Nanda G. Aduri, Cornelius Gati, Kritika Mohan, Lukas T. Henneberg, K. Christopher Garcia, Gita C. Abhiraman, Naotaka Tsutsumi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Models Molecular STAT3 Transcription Factor Cell type medicine.medical_treatment Interleukin-10 Receptor alpha Subunit CD8-Positive T-Lymphocytes Protein Engineering Monocytes Article Cell Line 03 medical and health sciences Mice 0302 clinical medicine Immune system Pleiotropy Sepsis medicine Animals Humans Myeloid Cells Protein Interaction Domains and Motifs Receptor Inflammation Multidisciplinary Binding Sites Chemistry Cryoelectron Microscopy Macrophage Activation Interleukin-10 Receptor beta Subunit Cell biology Interleukin-10 Interleukin 10 030104 developmental biology Cytokine 030220 oncology & carcinogenesis Cytokines Signal transduction Directed Molecular Evolution Protein Multimerization CD8 Protein Binding Signal Transduction |
| Zdroj: | Science |
| ISSN: | 1095-9203 |
| Popis: | Cryo-EM helps engineer enhanced IL-10 Interleukin-10 (IL-10) binds to the IL-10 receptor (IL-10R), comprising two high-affinity α chains and two low-affinity β chains. Depending on the cellular context of its recognition, IL-10 can either suppress or activate immune responses. This pleiotropic behavior has complicated efforts to use IL-10 as an anti-inflammatory agent. Saxton et al. generated a high-affinity version of IL-10 (super-10), which allowed them to visualize IL-10 in complex with both IL-10Rα and IL-10Rβ by cryo–electron microscopy (cryo-EM). This enabled them to engineer additional variants of IL-10 with variable IL-10Rβ–binding affinities. Some of the partial agonists exhibited biased actions on myeloid cells, which exhibited anti-inflammatory properties without concomitant CD8 T cell activation. These findings may serve as a blueprint for future enhanced cytokine–based therapeutics. Science , this issue p. eabc8433 |
| Databáze: | OpenAIRE |
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