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Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10.

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  • معلومة اضافية
    • المصدر:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE
    • بيانات النشر:
      Publication: : Washington, DC : American Association for the Advancement of Science
      Original Publication: New York, N.Y. : [s.n.] 1880-
    • الموضوع:
      Interleukin-10/*chemistry ; Interleukin-10/*metabolism; Animals ; Binding Sites ; CD8-Positive T-Lymphocytes/immunology ; Cell Line ; Cryoelectron Microscopy ; Cytokines/metabolism ; Directed Molecular Evolution ; Humans ; Inflammation ; Interleukin-10/agonists ; Interleukin-10 Receptor alpha Subunit/chemistry ; Interleukin-10 Receptor alpha Subunit/metabolism ; Interleukin-10 Receptor beta Subunit/chemistry ; Interleukin-10 Receptor beta Subunit/metabolism ; Macrophage Activation ; Mice ; Models, Molecular ; Monocytes/immunology ; Monocytes/metabolism ; Myeloid Cells/immunology ; Myeloid Cells/metabolism ; Protein Binding ; Protein Engineering ; Protein Interaction Domains and Motifs ; Protein Multimerization ; STAT3 Transcription Factor/metabolism ; Sepsis/immunology ; Signal Transduction
    • نبذة مختصرة :
      Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo-electron microscopy at a resolution of 3.5 angstroms. The hexameric structure shows how IL-10 and IL-10Rα form a composite surface to engage the shared signaling receptor IL-10Rβ, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rβ binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity. Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8 + T cells, thereby uncoupling the major opposing functions of IL-10. These results provide a mechanistic blueprint for tuning the pleiotropic actions of IL-10.
      (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
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    • Grant Information:
      T32 GM007365 United States GM NIGMS NIH HHS; U54 CA244711 United States CA NCI NIH HHS; United States HHMI Howard Hughes Medical Institute; R37 AI051321 United States AI NIAID NIH HHS; R01 AI051321 United States AI NIAID NIH HHS; R01 CA177684 United States CA NCI NIH HHS
    • الرقم المعرف:
      0 (Cytokines)
      0 (IL10 protein, human)
      0 (Interleukin-10 Receptor alpha Subunit)
      0 (Interleukin-10 Receptor beta Subunit)
      0 (STAT3 Transcription Factor)
      0 (STAT3 protein, human)
      130068-27-8 (Interleukin-10)
    • الموضوع:
      Date Created: 20210319 Date Completed: 20210326 Latest Revision: 20220716
    • الموضوع:
      20250114
    • الرقم المعرف:
      PMC9132103
    • الرقم المعرف:
      10.1126/science.abc8433
    • الرقم المعرف:
      33737461