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

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

  • Cytokine. 2015 Feb;71(2):238-45. doi: 10.1016/j.cyto.2014.10.032.
Shinichi Uchikawa 1,  Masaki Yoda 2,  Takahide Tohmonda 3,  Arihiko Kanaji 4,  Morio Matsumoto 5,  Yoshiaki Toyama 6,  Keisuke Horiuchi 7
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: shine1@yahoo.co.jp.
  • 2 Department of Anti-aging Orthopedic Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: yoda@a2.keio.jp.
  • 3 Department of Anti-aging Orthopedic Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: tohmonda@z7.keio.jp.
  • 4 Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: hikokanaji@gmail.com.
  • 5 Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: morio@a5.keio.jp.
  • 6 Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: toyama@z6.keio.jp.
  • 7 Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Anti-aging Orthopedic Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: horiuchi@z3.keio.jp.
PMID: 25461404 DOI: 10.1016/j.cyto.2014.10.032
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.

Keywords

ADAM17/TACE; Ectodomain shedding; IL-1 receptors.

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