ADAM17 regulates IL-1 signaling by selectively releasing IL-1 receptor type 2 from the cell surface

Shinichi Uchikawa, Masaki Yoda, Takahide Tohmonda, Arihiko Kanaji, Morio Matsumoto, Yoshiaki Toyama, Keisuke Horiuchi

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Interleukin (IL)-1 is one of the most evolutionarily conserved cytokines and plays an essential role in the regulation of innate immunity. IL-1 binds to two different receptors, IL-1R1 and IL-1R2, which share approximately 28% amino acid homology. IL-1R1 contains a cytoplasmic domain and is capable of transducing cellular signals; by contrast, IL-1R2 lacks a functional cytoplasmic domain and serves as a decoy receptor for IL-1. Interestingly, IL-1R2 is proteolytically cleaved and also functions as a soluble receptor that blocks IL-1 activity. In the present study, we examined the shedding properties of IL-1R2 and demonstrate that ADAM17 is de facto the major sheddase for IL-1R2 and that introducing a mutation into the juxta-membrane domain of IL-1R2 significantly desensitizes IL-1R2 to proteolytic cleavage. IL-1R1 was almost insensitive to ADAM17-dependent cleavage; however, the replacement of the juxta-membrane domain of IL-R1 with that of IL-1R2 significantly increased the sensitivity of IL-1R1 to shedding. Furthermore, we demonstrate that ADAM17 indirectly enhances IL-1 signaling in a cell-autonomous manner by selectively cleaving IL-1R2. Taken together, the data collected in the present study indicate that ADAM17 affects sensitivity to IL-1 by changing the balance between IL-1R1 and the decoy receptor IL-1R2.

Original languageEnglish
Pages (from-to)238-245
Number of pages8
JournalCytokine
Volume71
Issue number2
DOIs
Publication statusPublished - 2015 Feb 1

Keywords

  • ADAM17/TACE
  • Ectodomain shedding
  • IL-1 receptors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Biochemistry
  • Hematology
  • Molecular Biology

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