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Sci Rep. 2016 Aug 30;6:32259. doi: 10.1038/srep32259.

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

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Department of Orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa pref., 230-8501, Japan.
Tohoku University Hospital, Maxillo-Oral Disorders, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi pref. 980-8575, Japan.
Tohoku University Graduate School of Dentistry, Oral Microbiology, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi pref. 980-8575, Japan.
The Forsyth Institute, Department of Immunology and Infectious Diseases, 245 First Street, Cambridge, MA, 02142, USA.
Department Mineralized Tissue Biology, 245 First Street, Cambridge, MA 02142, USA.
Section of Fixed Prosthodontics, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan.
Harvard School of Dental Medicine, Department of Oral Medicine, Infection, and Immunity, Boston, MA 02115, USA.
Harvard School of Dental Medicine, Department of Developmental Biology, Boston, MA 02115, USA.


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.

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