Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional Toll/IL-1 receptor domain/BB-loop mimetics

Academic Article
uri icon
  • Overview
  • Research
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Davis, C. N.
  • Mann, E.
  • Behrens, M. M.
  • Gaidarova, S.
  • Rebek, M.
  • Rebek Jr., Julius
  • Bartfai, Tamas

publication date

  • February 2006

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Interleukin (IL)-1beta is a pluripotent proinflammatory cytokine that signals through the type-I IL-1 receptor (IL-1RI), a member of the Toll-like receptor family. In hypothalamic neurons, binding of IL-1beta to IL-1RI mediates transcription-dependent changes that depend on the recruitment of the cytosolic adaptor protein myeloid differentiation primary-response protein 88 (MyD88) to the IL-1RI/IL-1 receptor accessory protein (IL-1RAcP) complex through homomeric Toll/IL-1 receptor (TIR)-TIR interactions. Through design and synthesis of bifunctional TIR mimetics that disrupt the interaction of MyD88 with the IL-1RI/IL-1RAcP complex, we analyzed the involvement of MyD88 in the signaling of IL-1beta in anterior hypothalamic neurons. We show here that IL-1beta-mediated activation of the protein tyrosine kinase Src depended on a MyD88 interaction with the IL-1RI/IL-1RAcP complex. The activation of the protein kinase Akt/PKB depended on the recruitment of the p85 subunit of PI3K to IL-1RI and independent of MyD88 association with the IL-1RI/IL-1RAcP complex. These bifunctional TIR-TIR mimetics represent a class of low-molecular-weight compounds with both an antiinflammatory and neuroprotective potential. These compounds have the potential to inhibit the MyD88-dependent proinflammatory actions of IL-1beta, while permitting the potential neuronal survival supporting actions mediated by the MyD88-independent activation of the protein kinase Akt.

subject areas

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Anti-Inflammatory Agents
  • Biomimetic Materials
  • Interleukin-1
  • Mice
  • Myeloid Differentiation Factor 88
  • Neurons
  • Phosphatidylinositol 3-Kinases
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-akt
  • Receptors, Interleukin-1
  • Signal Transduction
  • Toll-Like Receptors
  • src-Family Kinases
scroll to property group menus

Research

keywords

  • cytokine
  • inflammation
  • interleukin
  • protein-protein interaction
scroll to property group menus

Identity

PubMed Central ID

  • PMC1413805

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0510802103

PubMed ID

  • 16477040
scroll to property group menus

Additional Document Info

start page

  • 2953

end page

  • 2958

volume

  • 103

issue

  • 8

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support