A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma

Hiroyuki Kanzaki, Fumiaki Shinohara, Maiko Suzuki, Satoshi Wada, Yutaka Miyamoto, Yuuki Yamaguchi, Yuta Katsumata, Seicho Makihira, Toshi Kawai, Martin A Taubman, Yoshiki Nakamura

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Interferon-gamma (IFN-γ) is a pleiotropic cytokine that exerts anti-tumor and anti-osteoclastogenic effects. Although transcriptional and post-transcriptional regulation of IFN-γ is well understood, subsequent modifications of secreted IFN-γ are not fully elucidated. Previous research indicates that some cancer cells escape immune surveillance and metastasize into bone tissue by inducing osteoclastic bone resorption. Peptidases of the a-disintegrin and metalloproteinase (ADAM) family are implicated in cancer cell proliferation and tumor progression. We hypothesized that the ADAM enzymes expressed by cancer cells degrades IFN-γ and attenuates IFN-γ-mediated anti-tumorigenic and anti-osteoclastogenic effects. Recombinant ADAM17 degraded IFN-γ into small fragments. The addition of ADAM17 to the culture supernatant of stimulated mouse splenocytes decreased IFN-γ concentration. However, ADAM17 inhibition in the stimulated mouse T-cells prevented IFN-γ degradation. ADAM17-expressing human breast cancer cell lines MCF-7 and MDA-MB-453 also degraded recombinant IFN-γ, but this was attenuated by ADAM17 inhibition. Degraded IFN-γ lost the functionality including the inhibititory effect on osteoclastogenesis. This is the first study to demonstrate the extracellular proteolytic degradation of IFN-γ by ADAM17. These results suggest that ADAM17-mediated degradation of IFN-γ may block the anti-tumorigenic and anti-osteoclastogenic effects of IFN-γ. ADAM17 inhibition may be useful for the treatment of attenuated cancer immune surveillance and/or bone metastases.

Original languageEnglish (US)
Pages (from-to)32259
JournalScientific Reports
Volume6
DOIs
StatePublished - Aug 30 2016
Externally publishedYes

Keywords

  • ADAM17 Protein/genetics
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal/immunology
  • Antibodies, Neutralizing/immunology
  • Breast Neoplasms/genetics
  • Cell Line, Tumor
  • Cells, Cultured
  • Humans
  • Interferon-gamma/genetics
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Proteolysis/drug effects
  • RAW 264.7 Cells
  • RNA Interference
  • Recombinant Proteins/metabolism
  • T-Lymphocytes/drug effects

Fingerprint Dive into the research topics of 'A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma'. Together they form a unique fingerprint.

  • Cite this

    Kanzaki, H., Shinohara, F., Suzuki, M., Wada, S., Miyamoto, Y., Yamaguchi, Y., Katsumata, Y., Makihira, S., Kawai, T., Taubman, M. A., & Nakamura, Y. (2016). A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma. Scientific Reports, 6, 32259. https://doi.org/10.1038/srep32259