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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.

Author information

1
Department of Orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa pref., 230-8501, Japan.
2
Tohoku University Hospital, Maxillo-Oral Disorders, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi pref. 980-8575, Japan.
3
Tohoku University Graduate School of Dentistry, Oral Microbiology, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi pref. 980-8575, Japan.
4
The Forsyth Institute, Department of Immunology and Infectious Diseases, 245 First Street, Cambridge, MA, 02142, USA.
5
Department Mineralized Tissue Biology, 245 First Street, Cambridge, MA 02142, USA.
6
Section of Fixed Prosthodontics, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan.
7
Harvard School of Dental Medicine, Department of Oral Medicine, Infection, and Immunity, Boston, MA 02115, USA.
8
Harvard School of Dental Medicine, Department of Developmental Biology, Boston, MA 02115, USA.

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.

PMID:
27573075
PMCID:
PMC5004192
DOI:
10.1038/srep32259
[Indexed for MEDLINE]
Free PMC Article

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