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

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Abstract

Interferon-gamma (IFN-Î 3) is a pleiotropic cytokine that exerts anti-tumor and anti-osteoclastogenic effects. Although transcriptional and post-transcriptional regulation of IFN-Î 3 is well understood, subsequent modifications of secreted IFN-Î 3 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-Î 3 and attenuates IFN-Î 3-mediated anti-tumorigenic and anti-osteoclastogenic effects. Recombinant ADAM17 degraded IFN-Î 3 into small fragments. The addition of ADAM17 to the culture supernatant of stimulated mouse splenocytes decreased IFN-Î 3 concentration. However, ADAM17 inhibition in the stimulated mouse T-cells prevented IFN-Î 3 degradation. ADAM17-expressing human breast cancer cell lines MCF-7 and MDA-MB-453 also degraded recombinant IFN-Î 3, but this was attenuated by ADAM17 inhibition. Degraded IFN-Î 3 lost the functionality including the inhibititory effect on osteoclastogenesis. This is the first study to demonstrate the extracellular proteolytic degradation of IFN-Î 3 by ADAM17. These results suggest that ADAM17-mediated degradation of IFN-Î 3 may block the anti-tumorigenic and anti-osteoclastogenic effects of IFN-Î 3. ADAM17 inhibition may be useful for the treatment of attenuated cancer immune surveillance and/or bone metastases.

Original languageEnglish
Article number32259
JournalScientific reports
Volume6
DOIs
Publication statusPublished - Aug 30 2016

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Kanzaki, H., Shinohara, F., Suzuki, M., Wada, S., Miyamoto, Y., Yamaguchi, Y., ... Nakamura, Y. (2016). A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma. Scientific reports, 6, [32259]. https://doi.org/10.1038/srep32259