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Identification of essential regions in the cytoplasmic tail of interleukin-1 receptor accessory protein critical for interleukin-1 signaling.

Interleukin (IL)-1 plays an important role in inflammation and regulation of immune responses. The activated IL-1 receptor complex, which consists of the IL-1 receptor type I and the IL-1 receptor accessory protein (IL-1RAcP), generates multiple cellular responses including NF-kappaB activation, IL-2 secretion, and IL-2 promoter activation. Reconstitution experiments in EL4D6/76 cells lacking IL-1RAcP expression and IL-1 responsiveness were used to analyze structure-function relationships of the IL-1RAcP cytoplasmic tail. Mutating a potential tyrosine kinase phosphorylation motif and various conserved amino acid (aa) residues had no effect on IL-1 responsiveness. Truncation analyses revealed that box 3 of the TIR domain was required for NF-kappaB activation, IL-2 production, and c-Jun N-terminal kinase (JNK) activation, whereas IL-2 promoter activation was only partially inhibited. Surprisingly, deletion of aa 527-534 resulted in almost complete loss of all IL-1 responsiveness. Replacement of these aa with alanyl residues did not reconstitute NF-kappaB activation, IL-2 production, or JNK activation but partly restored IL-2 promoter activation. Immunoprecipitation data revealed a strong correlation between MyD88 binding with NF-kappaB activation and IL-2 production but not with IL-2 promoter activation. Taken together, our data indicate that box 3 of IL-1RAcP is critical for IL-1-dependent NF-kappaB activation and stabilization of IL-2 mRNA via JNK, whereas aa 527-534 largely contribute to IL-2 promoter activation.

Pubmed ID: 11880380

Authors

  • Radons J
  • Gabler S
  • Wesche H
  • Korherr C
  • Hofmeister R
  • Falk W

Journal

The Journal of biological chemistry

Publication Data

May 10, 2002

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Cell Line
  • Cytoplasm
  • Enzyme Activation
  • Enzyme-Linked Immunosorbent Assay
  • Gene Deletion
  • Genes, Reporter
  • Humans
  • Interleukin-1
  • Interleukin-1 Receptor Accessory Protein
  • Interleukin-2
  • JNK Mitogen-Activated Protein Kinases
  • Luciferases
  • Mice
  • Mitogen-Activated Protein Kinases
  • Models, Biological
  • Molecular Sequence Data
  • Mutation
  • NF-kappa B
  • Plasmids
  • Precipitin Tests
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins
  • Signal Transduction
  • Structure-Activity Relationship
  • Time Factors
  • Transfection